Polymorphic forms of sodium benzoate and uses thereof

ABSTRACT

The present disclosure provides polymorphic forms of sodium benzoate with a X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of approximately 5.9, 30.2, and 31.2 degrees; or a X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of approximately 3.7, 5.9, and 26.6 degrees. The present disclosure provides polymorphic forms of sodium benzoate with a X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of approximately 3.6, 7.5, 26.6, and 29.4 degrees. Also provided herein are methods of preparing the polymorphic forms of sodium benzoate and uses thereof in treating and/or reducing the risk for a neuropsychiatric disorder (e.g., schizophrenia, psychotic disorders, depressive disorders, or Alzheimer&#39;s disease).

RELATED APPLICATION

The present application claims priority under 35 U.S.C. §§ 120 and365(c) to and is a continuation-in-part of international PCTApplication, PCT/CN2017/107436, filed Oct. 24, 2017, which claimspriority to U.S. application Ser. No. 15/452,137, filed Mar. 7, 2017 andU.S. Provisional Application No. 62/412,160, filed Oct. 24, 2016, eachof which is herein incorporated by reference in the entirety.

BACKGROUND OF THE INVENTION

The central nervous system (CNS) includes the brain and spinal cord. TheCNS is vulnerable to various disorders, which may be caused by variousfactors, including genetic, trauma, infections, degeneration, structuraldefects and/or damages, tumors, blood flow disruption, and autoimmunedisorders. Symptoms of a CNS disorder would depend on the area of thenervous system that is involved and the cause of the disorder.

The development of effective therapies for CNS disorders has laggedbehind other therapeutic areas due to the complexity of such disordersand the lack of efficient technology for delivering therapeutic agentsthrough the blood-brain barrier. As such, it is of great interest todevelop new treatment approaches for CNS disorders.

SUMMARY OF THE INVENTION

Provided herein are novel polymorphic forms of sodium benzoate,compositions and kits comprising such, methods of making such, and usesof the polymorphic forms of sodium benzoate for treating and/or reducingthe risk for a neuropsychiatric disorder (e.g., schizophrenia, psychoticdisorders, pain, or Alzheimer's disease). Also provided herein arepharmaceutical compositions comprising a sodium benzoate compound andclozapine; and a method for preventing, treating and/or reducing therisk of a neuropsychiatric disorder by administering such pharmaceuticalcompositions.

In one aspect, the present disclosure provides a polymorphic form ofsodium benzoate which has an X-ray powder diffraction pattern comprisingcharacteristic peaks at a reflection angle 2θ of approximately 5.9,30.2, and 31.2 degrees, which may be determined by a period of a scanspeed of about 0.1 to 0.3 seconds per step. In certain embodiments, theX-ray powder diffraction pattern of the polymorphic form of sodiumbenzoate may further comprise characteristic peaks at a reflection angle2θ of approximately 3.6, 7.2, 7.5, 14.9, 15.9, 16.6, 17.6, 18.8, 20.4,22.9, 23.7, 25.1, 25.8, 26.6, 28.1, 29.1, 29.4, 29.7, 31.5, 32.9, 34.2,and 35.7 degrees. In some embodiments, the X-ray powder diffractionpattern of the polymorphic form of sodium benzoate may further comprisecharacteristic peaks at a reflection angle 2θ of approximately 3.7, 6.8,7.5, 11.3, 11.6, 17.6, 22.7, 23.5, 26.2, 27.6, 28.3, 29.3, 32.2, 32.9,34.0, and 35.7 degrees. In some embodiments, the X-ray powderdiffraction pattern of the polymorphic form of sodium benzoate mayfurther comprise characteristic peaks at a reflection angle 2θ ofapproximately 3.7, 6.3, 6.8, 7.5, 11.7, 17.7, 23.6, 24.5, 26.5, 27.0,27.7, 28.4, 29.0, 31.0, 32.3, 34.2, and 35.9 degrees. In someembodiments, the X-ray powder diffraction pattern of the polymorphicform of sodium benzoate may further comprise characteristic peaks at areflection angle 2θ of approximately 4.3, 7.1, 8.6, 10.1, 10.7, 12.9,13.8, 14.4, 17.2, 17.7, 18.5, 21.5, 22.0, 22.6, 23.7, 25.1, 25.9, 26.2,26.9, 27.9, 28.2, 28.8, 29.1, 29.7, 33.2, 34.9, 35.8, 36.1, and 39.3degrees.

In another aspect, the present disclosure provides a polymorphic form ofsodium benzoate which has an X-ray powder diffraction pattern comprisingcharacteristic peaks at a reflection angle 2θ of approximately 3.7, 5.9,and 26.6 degrees. In some embodiments, the X-ray diffraction pattern maybe determined by a period of a scan speed of about 0.1 to 0.3 secondsper step. In some embodiments, a X-ray powder diffraction pattern of thepolymorphic form of sodium benzoate may further comprise characteristicpeaks at a reflection angle 2θ of approximately 5.5, 6.7, 7.4, 12.5,14.7, 16.5, 17.7, 22.0, 23.6, 24.6, 25.8, 27.6, 28.4, 30.2, 31.1, 32.3,34.3, and 35.9 degrees. In some embodiments, the X-ray powderdiffraction pattern of the polymorphic form of sodium benzoate mayfurther comprise characteristic peaks at a reflection angle 2θ ofapproximately 6.6, 7.4, 9.4, 11.2, 12.5, 22.8, 25.1, 26.3, 28.2, 29.5,30.2, 31.1, 31.2, 33.0, and 34.0 degrees.

In one aspect, the present disclosure provides a polymorphic form ofsodium benzoate which has an X-ray powder diffraction pattern comprisingcharacteristic peaks at a reflection angle 2θ of approximately 3.6, 7.5,26.6, and 29.4 degrees; wherein the X-ray diffraction pattern isdetermined by a period of a scan speed of about 1.0 second per step. Incertain embodiments, the X-ray powder diffraction pattern of thepolymorphic form of sodium benzoate may further comprise characteristicpeaks at a reflection angle 2θ of approximately 5.9, 6.8, 17.6, 27.6,30.2, 30.9, and 32.3 degrees. In certain embodiments, the X-ray powderdiffraction pattern of the polymorphic form of sodium benzoate mayfurther comprise characteristic peaks at a reflection angle 2θ ofapproximately 11.1, 14.9, 26.2, 32.9, and 35.7 degrees. In certainembodiments, the X-ray powder diffraction pattern of the polymorphicform of sodium benzoate may further comprise characteristic peaks at areflection angle 2θ of approximately 12.4 and 22.9 degrees, In certainembodiments, the X-ray powder diffraction pattern of the polymorphicform of sodium benzoate may further comprise characteristic peaks at areflection angle 2θ of approximately 4.2, 8.5, 9.2, 11.1, 11.7, 12.4,14.9, 15.9, 16.6, 18.8, 19.4, 20.4, 21.6, 22.9, 23.7, 24.7, 25.1, 25.8,26.1, 28.1, 29.1, 29.7, 30.6, 31.5, 32.9, 33.6, 34.2, 35.7, 38.6, and39.6 degrees. In certain embodiments, the X-ray powder diffractionpattern of the polymorphic form of sodium benzoate may further comprisecharacteristic peaks at a reflection angle 2θ of approximately 8.9,11.1, 14.9, 22.7, 23.5, 24.8, 26.2, 28.3, 32.9, 34.0, 35.7, and 37.8degrees. In certain embodiments, the X-ray powder diffraction pattern ofthe polymorphic form of sodium benzoate may further comprisecharacteristic peaks at a reflection angle 2θ of approximately 6.3, 9.4,11.7, 16.4, 23.6, 24.5, 25.7, 28.4, 29.0, 30.4, 31.0, 31.2, 34.2, 35.4,and 35.9 degrees. In certain embodiments, the X-ray powder diffractionpattern of the polymorphic form of sodium benzoate may further comprisecharacteristic peaks at a reflection angle 2θ of approximately 4.2, 5.6,5.9, 6.6, 8.4, 9.4, 12.5, 17.6, 18.6, 21.6, 22.8, 23.6, 25.1, 27.1,28.2, 30.2, 31.1, 31.3, 32.0, 34.0, and 38.0 degrees.

In another aspect, the present disclosure provides compositions (e.g., apharmaceutical composition, a nutraceutical composition, a health food,or a medical food) including (i) an effective amount of one or more ofthe polymorphic forms of sodium benzoate described herein, and (ii) acarrier, excipient, diluent, binder, additive, filler, lubricant, or amixture thereof. An effective amount described herein may be atherapeutically effective amount or prophylactically effective amount.

In yet another aspect, the present disclosure provides methods fortreating and/or reducing the risk for a neuropsychiatric disorder (e.g.,schizophrenia, psychotic disorders, depression, pain, Alzheimer'sdisease, or dementia), the method comprising administering to a subjectin need of the treatment an effective amount of any of the compositionsdescribed herein.

A target neuropsychiatric disorder can include, but is not limited to,schizophrenia, psychotic disorders, Alzheimer's disease, dementia,frontotemporal dementia, mild cognitive impairment, benignforgetfulness, closed head injury, autistic spectrum disorder,Asperger's disorder, attention deficit hyperactivity disorders,obsessive compulsive disorder, tic disorders, childhood learningdisorders, premenstrual syndrome, depression, suicidal ideation,suicidal behavior, bipolar disorder, anxiety disorders, post-traumaticstress disorder, chronic pain, eating disorders, addiction disorders,personality disorders, Parkinson's disorder, Huntington's disorder,multiple sclerosis, or amyotrophic lateral sclerosis.

In any of the treatment methods as described herein, the subject beingtreated can be a mammal (e.g., human or non-human mammal). For example,the subject can be a human patient having or suspected of having atarget disease as described herein.

Another aspect of the present disclosure relates to kits comprising acontainer in which a polymorphic form of sodium benzoate, or compositionthereof, as described herein, is placed. The kits described herein mayinclude a single dose or multiple doses of the polymorph or composition.The kits may be useful in a method of the disclosure. In certainembodiments, the kit further includes instructions for using thepolymorph or composition.

In yet another aspect, the present disclosure provides polymorphic formsof sodium benzoate and compositions described herein for use in treatingand/or reducing the risk for a neuropsychiatric disorder as describedherein. The present disclosure also provides uses of one or more of thepolymorphic form of sodium benzoate for manufacturing a medicament foruse in treating a target neuropsychiatric disorder as described herein.

The present disclosure also provides methods for preparing the novelpolymorphic forms of sodium benzoate described herein.

In some embodiments, provided herein is a method for preparing apolymorphic form of sodium benzoate, the method comprising: (i)dissolving an excess amount of sodium benzoate in a single or mixedsolvent to form a saturated solution at ambient pressure andtemperature, (ii) filtrating the saturated solution to remove insolublecomponents; (iii) evaporating the saturated solution obtained in (ii) toform a polymorphic form of sodium benzoate at ambient or reducedpressure and at an elevated temperature of approximately 40-110° C.; and(vi) collecting the polymorphic form of sodium benzoate formed in (iii).

In other embodiments, provided herein is a method for preparing apolymorphic form of sodium benzoate, the method comprising: (i)dissolving sodium benzoate in a single or mixed solvent at a temperatureranging from about 50-110° C. to form a solution; (ii) cooling thesolution to ambient temperature while stirring; (iii) placing the cooledsolution at ambient temperature to allow formation of a polymorphic formof sodium benzoate; and (iv) collecting the polymorphic form of sodiumbenzoate formed in (iii).

In yet other embodiments, provided herein is a method for preparing apolymorphic form of sodium benzoate, the method comprising: (i) placingsodium benzoate at a relative humidity (RH) greater than about 90% forabout 1 to 10 days, during which a polymorphic form of sodium benzoateforms; and (ii) collecting the polymorphic form of sodium benzoateformed in (i).

In other embodiments, provided herein is a method for preparing apolymorphic form of sodium benzoate, the method comprising: (i)dissolving sodium benzoate in a polar solvent, to form a slurry; (ii)stirring the slurry for approximately 10 minutes to approximately 6 daysto produce the polymorphic form of sodium benzoate, and (iii) filteringand collecting the polymorphic form of sodium benzoate thus formed. Insome embodiments, the sodium benzoate is dissolved in methanol in step(i) of the method. In some embodiments, the polar solvent may comprisemethanol, acetonitrile, or isobutanol, or a combination thereof. In someembodiments, the polar solvent comprises water. In some embodiments, thepolar solvent does not comprise water. In some embodiments, the polarsolvent comprises methanol, acetonitrile, or isobutanol, or acombination thereof, and no water.

In some embodiments, in step (i), the solvent comprises methanol and themethod further comprises adding acetonitrile after the sodium benzoateis dissolved in the solvent in step (i). In some embodiments, the sodiumbenzoate is dissolved in methanol in step (i) of the method and whereinin step (ii) the stirring of the slurry is for approximately 10 minutes,or for approximately 2 days to approximately 6 days. In someembodiments, the sodium benzoate is dissolved in methanol in step (i) ofthe method and wherein in step (ii) the stirring of the slurry is forapproximately 10 minutes, or for approximately 2 days to approximately 4days. In some embodiments, the sodium benzoate is dissolved in methanolin step (i) of the method and wherein in step (ii) the stirring of theslurry is for approximately 10 minutes. In some embodiments, in step(i), the solvent comprises acetonitrile. In some embodiments, the sodiumbenzoate is dissolved in acetonitrile in step (i) of the method andwherein in step (ii) the stirring of the slurry is for approximately 2days. In some embodiments, the sodium benzoate is dissolved inacetonitrile in step (i) of the method and wherein in step (ii) thestirring of the slurry is for approximately 2 days to approximately 4days. In some embodiments, in step (i), the solvent comprisesisobutanol. In some embodiments, the sodium benzoate is dissolved inisobutanol in step (i) of the method and wherein in step (ii) thestirring of the slurry is for approximately 2 days to approximately 6days. In some embodiments, the sodium benzoate is dissolved inisobutanol in step (i) of the method and wherein in step (ii) thestirring of the slurry is for approximately 4 days to approximately 6days. In some embodiments, the sodium benzoate is dissolved inisobutanol in step (i) of the method and wherein in step (ii) thestirring of the slurry is for approximately 6 days. In some embodiments,wherein the sodium benzoate is dissolved in methanol in step (i) of themethod, wherein step (ii) comprises further adding the acetonitrileafter the sodium benzoate is dissolved in methanol, and wherein in step(ii) the stirring of the slurry is for approximately 2 days. In someembodiments, wherein the sodium benzoate is dissolved in methanol instep (i) of the method, wherein step (ii) comprises further adding theacetonitrile after the sodium benzoate is dissolved in methanol, andwherein in step (ii) the stirring of the slurry is for approximately 2days to approximately 6 days. In some embodiments, in the process, thesodium benzoate is dissolved in methanol in step (i) of the method, theprocess further comprises adding acetonitrile after the sodium benzoateis dissolved in methanol in step (i) of the method, and wherein in step(ii) the stirring of the slurry is for approximately 2 days toapproximately 4 days.

Alternatively, one or more polymorphic forms of sodium benzoatedescribed herein can be prepared by a method comprising: (i) preparing aslurry of sodium benzoate in a single or mixed solvent; (ii) stirringthe slurry for 6 hours to 10 days, during which a polymorphic form ofsodium benzoate forms; and (iii) collecting the polymorphic form ofsodium benzoate formed in (ii).

In other examples, such a method may comprise: (i) dissolving sodiumbenzoate in a single or mixed solvent to form a solution; (ii) mixing ananti-solvent with the solution obtained in (i) to form a slurry, whereinthe volume ratio between the anti-solvent and the solution in (i) isabout 4:1 to 15:1; (iii) stirring the slurry at ambient pressure andtemperature for about 2-10 days, during which a polymorphic form ofsodium benzoate forms; and (iv) collecting the polymorphic form ofsodium benzoate formed in (iii).

In still other examples, the preparation method may comprise: (i)preparing a slurry of any suitable polymorphic form of sodium benzoateas described herein in a single or mixed solvent in the presence ofabout 2-10% of water; (ii) stirring the slurry at ambient pressure andtemperature for about 2 to 10 days, during which a polymorphic form ofsodium benzoate forms; and (iii) collecting the polymorphic form ofsodium benzoate formed in (iii).

In yet another aspect, the present disclosure provides a pharmaceuticalcomposition comprising 50 to 1000 mg of a sodium benzoate compound and25 to 300 mg of clozapine in a solid dosage form, e.g., tablet, dragee,capsule, pill, powder, or granule. In some embodiments, the solid dosageform may further comprise a film coating.

The aforementioned sodium benzoate compound can be in amorphous form, inpolymorphic forms, or both. In some embodiments, the sodium benzoatecompound comprises any of the polymorphic forms of sodium benzoatedescribed herein (e.g., polymorph #4).

Any of the pharmaceutical compositions described herein may furthercomprise a pharmaceutically acceptable excipient, which may be boricacid, sodium alginate, sodium citrate, sodium hyaluronate, chitosan,magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide,talc, sodium starch glycolate, croscarmellose, crospovidone, tannicacid, or a combination thereof. In some embodiments, the pharmaceuticalcomposition may comprise 50 to 1000 mg of sodium benzoate, 25-300 mg ofclozapine, 50-500 mg of sodium alginate, 50-400 mg of sodium citrate,5-100 mg of magnesium stearate, and 80-200 mg of sodium starchglycolate.

In another aspect, the present disclosure provides a method for treatingand/or reducing the risk for a neuropsychiatric disorder, whichcomprises administering to a subject in need of the treatment aneffective amount of any of the pharmaceutical compositions describedherein. Target neuropsychiatric disorders include, but are not limitedto, schizophrenia, psychotic disorders, Alzheimer's disease, dementia,frontotemporal dementia, mild cognitive impairment, benignforgetfulness, closed head injury, autistic spectrum disorder,Asperger's disorder, attention deficit hyperactivity disorders,obsessive compulsive disorder, tic disorders, childhood learningdisorders, premenstrual syndrome, depression, suicidal ideation and/orbehaviors, bipolar disorder, anxiety disorders, post-traumatic stressdisorder, chronic pain, eating disorders, addiction disorders,personality disorders, Parkinson's disorder, Huntington's disorder,multiple sclerosis, or amyotrophic lateral sclerosis.

In some embodiments, the subject can be a human patient having,suspected of having, or at risk for the neuropsychiatric disorder. Thepharmaceutical composition may be administered to the subject by asystemic route, e.g., enteral administration or parenteraladministration. In some instances, the subject is administered thepharmaceutical composition at a frequency of four times a day to onetime two months. Alternatively or in addition, the subject is treatedconcurrently with, prior to, or subsequent to one or more additionaltherapeutic agents for treating and/or reducing the risk for theneuropsychiatric disorder.

Also within the present disclosure are any of the pharmaceuticalcompositions described herein for use in treating a neuropsychiatricdisorder, and uses of such for manufacturing a medicament for treatingthe target disease.

The details of one or more embodiments of the disclosure are set forthherein. Other features, objects, and advantages of the disclosure willbe apparent from the Detailed Description, the Examples, and the Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

“Sodium benzoate” refers to a compound of the formula

The term “clozapine” refers to the compound with the IAPUC name of3-chloro-6-(4-methylpiperazin-1-yl)-5H-benzo[b][1,4]benzodiazepine.

The term “commercially available sodium benzoate” refers to sodiumbenzoate available from commercial source, which may be in amorphousform, may comprise a known single polymorphic form, or may comprise amixture of amorphous and/or one or more polymorphic forms.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO),tetrahydrofuran (THF), diethyl ether, and the like. The compoundsdescribed herein may be prepared, e.g., in crystalline form, and may besolvated. Suitable solvates include pharmaceutically acceptable solvatesand further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Representativesolvates include hydrates, ethanolates, and methanolates.

The term “crystalline” or “crystalline form” refers to a solid formsubstantially exhibiting three-dimensional order. In certainembodiments, a crystalline form of a solid is a solid form that issubstantially not amorphous. In certain embodiments, the X-ray powderdiffraction (XRPD) pattern of a crystalline form includes one or moresharply defined peaks.

The term “amorphous” or “amorphous form” refers to a form of a solid(“solid form”), the form substantially lacking three-dimensional order.In certain embodiments, an amorphous form of a solid is a solid formthat is substantially not crystalline. In certain embodiments, the X-raypowder diffraction (XRPD) pattern of an amorphous form includes a widescattering band with a peak at 2θ of, e.g., between 20 and 70°,inclusive, using CuKα radiation. In certain embodiments, the XRPDpattern of an amorphous form further includes one or more peaksattributed to crystalline structures. In certain embodiments, themaximum intensity of any one of the one or more peaks attributed tocrystalline structures observed at a 20 of between 20 and 70°,inclusive, is not more than 300-fold, not more than 100-fold, not morethan 30-fold, not more than 10-fold, or not more than 3-fold of themaximum intensity of the wide scattering band. In certain embodiments,the XRPD pattern of an amorphous form includes no peaks attributed tocrystalline structures.

The term “polymorph” or “polymorphic form” refers to a crystalline formof a compound (or a salt, hydrate, or solvate thereof). All polymorphicforms have the same elemental composition. Different crystalline formsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Recrystallization solvent, rateof crystallization, storage temperature, and other factors may cause onecrystal form to dominate. Various polymorphic forms of a compound can beprepared by crystallization under different conditions.

The terms “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a polymorphic form to reduce, slow, halt or preventactivity of a particular biological process in a cell relative tovehicle.

When a polymorphic form, pharmaceutical composition, method, use, or kitis referred to as “selectively,” “specifically,” or “competitively”binding a first protein, the polymorphic form binds the first proteinwith a higher binding affinity (e.g., not less than about 2-fold, notless than about 5-fold, not less than about 10-fold, not less than about30-fold, not less than about 100-fold, not less than about 1,000-fold,or not less than about 10,000-fold) than binding a second protein orthat is different from the first protein. When a polymorphic form isreferred to as “selectively,” “specifically,” or “competitively”modulating (e.g., increasing or inhibiting) the activity of a firstprotein, the polymorphic form modulates the activity of the firstprotein to a greater extent (e.g., not less than about 2-fold, not lessthan about 5-fold, not less than about 10-fold, not less than about30-fold, not less than about 100-fold, not less than about 1,000-fold,or not less than about 10,000-fold) than the activity of at least oneprotein that is different from the first protein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

The terms “solvent” and “anti-solvent” refer to either conventional ornon-conventional solvents including but not limited to water, acetone,acetonitrile, butanol, dioxane, ethanol, ethyl acetate, isobutanol,isopropanol, methanol, methyl ethyl ketone, methyl-1-butanol, methylt-butyl ether, tetrahydrofuran, and toluene. The term “solvent” refersto a substance (e.g., a liquid) added to dissolve a solute (anothersubstance (e.g., a solid)), to form a solution. The term “anti-solvent”refers to a solvent in which a solute is less soluble.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. A “patient”refers to a human subject in need of treatment of a disease. Forexample, the subject can be a human patient having, suspected of having,or at risk for a target disease as described herein.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a polymorphic form of sodium benzoate described herein, or acomposition thereof, in or on a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen) to delay or prevent disease occurrence.Treatment may also be continued after symptoms have resolved, forexample, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of any of the active ingredients described herein(e.g. any of the sodium benzoate compounds and/or clozapine) refers toan amount sufficient to elicit the desired biological response, i.e.,treating the condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of any of the active ingredientsdescribed herein may vary depending on such factors as the desiredbiological endpoint, the pharmacokinetics of the polymorphic form, thecondition being treated, the mode of administration, and the age andhealth of the subject. In certain embodiments, an effective amount is atherapeutically effective amount. In certain embodiments, an effectiveamount is a prophylactically effective amount. In certain embodiments,an effective amount is the amount of any of the active ingredientsdescribed herein in a single dose. In certain embodiments, an effectiveamount is the combined amounts of the active ingredients describedherein in multiple doses.

A “therapeutically effective amount” of any of the active ingredientsdescribed herein is an amount sufficient to provide a therapeuticbenefit in the treatment of a condition or to delay or minimize one ormore symptoms associated with the condition. A therapeutically effectiveamount of any of the active ingredients means an amount of therapeuticagent, alone or in combination with other therapies, which provides atherapeutic benefit in the treatment of the condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms, signs, or causes of thecondition, and/or enhances the therapeutic efficacy of anothertherapeutic agent.

A “prophylactically effective amount” of any of the active ingredientsdescribed herein is an amount sufficient to prevent a condition, or oneor more symptoms associated with the condition or prevent itsrecurrence. A prophylactically effective amount of any of the activeingredients means an amount of a therapeutic agent, alone or incombination with other agents, which provides a prophylactic benefit inthe prevention of the condition. The term “prophylactically effectiveamount” can encompass an amount that improves overall prophylaxis orenhances the prophylactic efficacy of another prophylactic agent.

The terms “about” or “approximately,” which are used interchangeablyherein, means within an acceptable error range for the particular valueas determined by one of ordinary skill in the art, which will depend inpart on how the value is measured or determined, i.e., the limitationsof the measurement system. For example, “about” or “approximately” canmean a range of less than ±10%, preferably less than ±5%, morepreferably less than ±1%, more preferably less than ±0.5% of a givenvalue. Where particular values are described in the application andclaims, unless otherwise stated, the term “about” is implicit and inthis context means within an acceptable error range for the particularvalue.

The term “neurological disease” refers to any disease of the nervoussystem, including diseases that involve the central nervous system(brain, brainstem, spinal cord, and cerebellum), the peripheral nervoussystem (including cranial nerves), and the autonomic nervous system(parts of which are located in both central and peripheral nervoussystem). Neurodegenerative diseases refer to a type of neurologicaldisease marked by the loss of nerve cells, including, but not limitedto, Alzheimer's disease, Parkinson's disease, frontotemporal dementia,multiple sclerosis, amyotrophic lateral sclerosis, tauopathies(including frontotemporal dementia), multiple system atrophy, andHuntington's disease. Examples of neurological diseases include, but arenot limited to, headache, stupor and coma, dementia, seizure, sleepdisorders, trauma, infections, neoplasms, neuro-ophthalmopathy, movementdisorders, demyelinating diseases, spinal cord disorders, and disordersof peripheral nerves, muscle and neuromuscular junctions. Addiction andmental illness, include, but are not limited to, bipolar disorder,depression and schizophrenia, are also included in the definition of CNSdiseases. Further examples of neurological diseases include acquiredepileptiform aphasia; acute disseminated encephalomyelitis;adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardisyndrome; Alexander disease; Alpers' disease; alternating hemiplegia;Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly;Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoidcysts; arachnoiditis; Arnold-Chiari malformation; arteriovenousmalformation; Asperger syndrome; ataxia telangiectasia; attentiondeficit hyperactivity disorder; autism; autonomic dysfunction; backpain; Batten disease; Behcet's disease; Bell's palsy; benign essentialblepharospasm; benign focal amyotrophy; benign intracranialhypertension; Binswanger's disease; blepharospasm; Bloch Sulzbergersyndrome; brachial plexus injury; brain abscess; brain injury; braintumors (including glioblastoma multiforme); spinal cord tumor;Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS);causalgia; central pain syndrome; central pontine myelinolysis; cephalicdisorder; cerebral aneurysm; cerebral arteriosclerosis; cerebralatrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Toothdisease; chemotherapy-induced neuropathy and neuropathic pain; Chiarimalformation; chorea; chronic inflammatory demyelinating polyneuropathy(CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowrysyndrome; coma, including persistent vegetative state; congenital facialdiplegia; corticobasal degeneration; cranial arteritis;craniosynostosis; Creutzfeldt-Jakob disease; cumulative traumadisorders; Cushing's syndrome; cytomegalic inclusion body disease(CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy;diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; earlyinfantile epileptic encephalopathy; empty sella syndrome; encephalitis;encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy;essential tremor; Fabry's disease; Fahr's syndrome; fainting; familialspastic paralysis; febrile seizures; Fisher syndrome; Friedreich'sataxia; frontotemporal dementia and other “tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; giant cell arteritis; giant cellinclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury;headache; hemifacial spasm; hereditary spastic paraplegia; heredopathiaatactica polyneuritiformis; herpes zoster oticus; herpes zoster;Hirayama syndrome; HIV-associated dementia and neuropathy (see alsoneurological manifestations of AIDS); holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; hydranencephaly;hydrocephalus; hypercortisolism; hypoxia; immune-mediatedencephalomyelitis; inclusion body myositis; incontinentia pigmenti;infantile phytanic acid storage disease; Infantile Refsum disease;infantile spasms; inflammatory myopathy; intracranial cyst; intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; lateral medullary(Wallenberg) syndrome; learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodydementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (akamotor neuron disease or amyotrophic lateral sclerosis); lumbar discdisease; lyme disease-neurological sequelae; Machado-Joseph disease;macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; meningitis; Menkes disease; metachromatic leukodystrophy;microcephaly; migraine; Miller Fisher syndrome; mini-strokes;mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motorneurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarctdementia; multifocal motor neuropathy; multiple sclerosis and otherdemyelinating disorders; multiple system atrophy with posturalhypotension; muscular dystrophy; myasthenia gravis; myelinoclasticdiffuse sclerosis; myoclonic encephalopathy of infants; myoclonus;myopathy; myotonia congenital; narcolepsy; neurofibromatosis;neuroleptic malignant syndrome; neurological manifestations of AIDS;neurological sequelae of lupus; neuromyotonia; neuronal ceroidlipofuscinosis; neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinaldysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy;opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overusesyndrome; paresthesia; Parkinson's disease; paramyotonia congenita;paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy;painful neuropathy and neuropathic pain; persistent vegetative state;pervasive developmental disorders; photic sneeze reflex; phytanic acidstorage disease; Pick's disease; pinched nerve; pituitary tumors;polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia(PHN); postinfectious encephalomyelitis; postural hypotension;Prader-Willi syndrome; primary lateral sclerosis; prion diseases;progressive; hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; stiff-person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy;sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachsdisease; temporal arteritis; tethered spinal cord syndrome; Thomsendisease; thoracic outlet syndrome; tic douloureux; Todd's paralysis;Tourette syndrome; transient ischemic attack; transmissible spongiformencephalopathies; transverse myelitis; traumatic brain injury; tremor;trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis;vascular dementia (multi-infarct dementia); vasculitis includingtemporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

The term “psychiatric disorder” refers to mental disorders and includesdiseases and disorders listed in the Diagnostic and Statistical Manualof Mental Disorders—Fourth Edition and Fifth Edition (DSM-IV, DSM-V),published by the American Psychiatric Association, Washington D.C.(1994, 2013). Psychiatric disorders include, but are not limited to,anxiety disorders (e.g., acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic disorder,posttraumatic stress disorder, separation anxiety disorder, socialphobia, and specific phobia), childhood disorders, (e.g.,attention-deficit/hyperactivity disorder, conduct disorder, andoppositional defiant disorder), eating disorders (e.g., anorexia nervosaand bulimia nervosa), mood disorders (e.g., depression, bipolar disorderI and II, cyclothymic disorder, dysthymic disorder, and major depressivedisorder), personality disorders (e.g., antisocial personality disorder,avoidant personality disorder, borderline personality disorder,dependent personality disorder, histrionic personality disorder,narcissistic personality disorder, obsessive-compulsive personalitydisorder, paranoid personality disorder, schizoid personality disorder,and schizotypal personality disorder), psychotic disorders (e.g., briefpsychotic disorder, delusional disorder, schizoaffective disorder,schizophreniform disorder, schizophrenia, and shared psychoticdisorder), substance-related disorders (e.g., alcohol dependence orabuse, amphetamine dependence or abuse, Cannabis dependence or abuse,cocaine dependence or abuse, hallucinogen dependence or abuse, inhalantdependence or abuse, nicotine dependence or abuse, opioid dependence orabuse, phencyclidine dependence or abuse, and sedative dependence orabuse), adjustment disorders, autism, Asperger's disorder, delirium,dementia, multi-infarct dementia, learning and memory disorders (e.g.,amnesia and age-related memory loss), tic disorder and Tourette'sdisorder.

As used herein, the term “personality disorders” refers to mentaldisorders characterized by enduring maladaptive patterns of behavior,cognition, and inner experience, exhibited across many contexts anddeviating markedly from those accepted by the individual's culture.These patterns develop early, are inflexible, and are associated withsignificant distress or disability. For example, the personalitydisorders can include, but not limited to, paranoid, schizoid,schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant,dependent, and obsessive-compulsive personality disorder.

The term “neuropsychiatric disorder,” including either neurologicaldiseases or psychiatric disorders or central nervous system disorders(CNS disorders), refers to a disorder that involves either psychiatricsymptoms or syndromes caused by organic central nervous systemdisorders. The main characteristics of neuropsychiatric symptoms includeoccurrence of the various psychiatric symptoms, cognitive impairment,neurological symptoms or the possibility of early cerebral developmentsymptoms.

The terms “health food” or “health food product” refers to any kind ofliquid and solid/semi-solid materials that are used for nourishinghumans and animals, for improving basic behavioral functioning,hyperactivity, mood, anxiety, depression, sensory perception,sensorimotor gating, pain threshold, memory and/or cognitivefunctioning, body weight, or for facilitating treatment of any of thetarget diseases noted herein. The term “nutraceutical composition”refers to compositions containing components from food sources andconferring extra health benefits in addition to the basic nutritionalvalue found in foods.

The term “medical food product” refers to a food product formulated tobe consumed or administered enterally, including a food product that isusually used under the supervision of a physician for the specificdietary management of a target disease, such as those described herein.A “medical food product” composition may refer to a composition that isspecially formulated and processed (as opposed to a naturally occurringfoodstuff used in a natural state) for a patient in need of thetreatment (e.g., human patients who suffer from illness or who requiresuse of the product as a major active agent for alleviating a disease orcondition via specific dietary management).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction (XRPD) of polymorphic form #1of sodium benzoate from Example 1, with peaks (°) of: 3.6, 5.9, 7.2,7.5, 14.9, 15.9, 16.6, 17.6, 18.8, 20.4, 22.9, 23.7, 25.1, 25.8, 26.6,28.1, 29.1, 29.4, 29.7, 30.2, 31.2, 31.5, 32.9, 34.2, and 35.7.

FIG. 2 shows the Thermogravimetric Analysis (TGA) of polymorphic form #1of sodium benzoate from Example 1.

FIG. 3 shows the profile determined by the differential scanningcalorimeter method (DSC), of polymorphic form #1 of sodium benzoate fromExample 1.

FIG. 4 shows the X-ray powder diffraction (XRPD) of polymorphic form #2of sodium benzoate from Example 2, with peaks (°) of: 3.7, 5.9, 6.8,7.5, 11.3, 11.6, 17.6, 22.7, 23.5, 26.2, 27.6, 28.3, 29.3; 30.2, 31.2,32.2, 32.9, 34.0, and 35.7.

FIG. 5 shows the Thermogravimetric Analysis (TGA) of polymorphic form #2of sodium benzoate from Example 2.

FIG. 6 shows the profile determined by the differential scanningcalorimeter method (DSC), of polymorphic form #2 of sodium benzoate fromExample 2.

FIG. 7 shows the X-ray powder diffraction (XRPD) of polymorphic form #3of sodium benzoate from Example 3, with peaks (°) of: 3.7, 5.9, 6.3,6.8, 7.5, 11.7, 17.7, 23.6, 24.5, 26.5, 27.0, 27.7, 28.4, 29.0, 30.2;31.0, 31.2, 32.3, 34.2, and 35.9.

FIG. 8 shows the Thermogravimetric Analysis (TGA) of polymorphic form #3of sodium benzoate from Example 3.

FIG. 9 shows the profile determined by the differential scanningcalorimeter method (DSC), of polymorphic form #3 of sodium benzoate fromExample 3.

FIG. 10 shows the X-ray powder diffraction (XRPD) of polymorphic form #4of sodium benzoate from Example 4, with peaks (°) of: 4.3, 5.9, 7.1,8.6, 10.1, 10.7, 12.9, 13.8, 14.4, 17.2, 17.7, 18.5, 21.5, 22.0, 22.6,23.7, 25.1, 25.9, 26.2, 26.9, 27.9, 28.2, 28.8, 29.1, 29.7, 30.2, 31.2,33.2, 34.9, 35.8, 36.1, and 39.3.

FIG. 11 shows the Thermogravimetric Analysis (TGA) of polymorphic form#4 of sodium benzoate from Example 4.

FIG. 12 shows the profile determined by the differential scanningcalorimeter method (DSC), of polymorphic form #4 of sodium benzoate fromExample 4.

FIG. 13 shows the X-ray powder diffraction (XRPD) of polymorphic form #5of sodium benzoate from Example 5, with peaks (°) of: 3.7, 5.5, 5.9,6.7, 7.4, 12.5, 14.7, 16.5, 17.7, 22.0, 23.6, 24.6, 25.8, 26.6, 27.6,28.4, 30.2, 31.1, 32.3, 34.3, and 35.9.

FIG. 14 shows the Thermogravimetric Analysis (TGA) of polymorphic form#5 of sodium benzoate from Example 5.

FIG. 15 shows the melting point, as determined by the differentialscanning calorimeter method (DSC), of polymorphic form #5 of sodiumbenzoate from Example 5.

FIG. 16 shows the X-ray powder diffraction (XRPD) of polymorphic form #6of sodium benzoate from Example 6, with peaks (°) of: 3.7, 5.9, 6.6,7.4, 9.4, 11.2, 12.5, 22.8, 25.1, 26.3, 28.2, 29.5, 30.2, 31.1, 31.2,33.0, and 34.0.

FIG. 17 shows the Thermogravimetric Analysis (TGA) of polymorphic form#6 of sodium benzoate from Example 6.

FIG. 18 shows the melting point, as determined by the differentialscanning calorimeter method (DSC), of polymorphic form #6 of sodiumbenzoate from Example 6.

FIG. 19 shows the X-ray powder diffraction (XRPD) of sodium benzoate(NaBen) from Merck, Formosa Laboratories, and new polymorphic form #4under high humidity conditions of over 90% relative humidity for 5 days.The XRPD of the sodium benzoate from Merck and Formosa Laboratories showchanges in XRPD under these high humidity conditions, but the XRPD ofpolymorphic form #4 of sodium benzoate from Example 7 does not show suchchanges in XRPD.

FIG. 20 shows the changes of X-ray powder diffraction (XRPD) of sodiumbenzoate (NaBen) from Merck combined with clozapine (300 mg) under highhumidity conditions (of over 90% relative humidity) for 5 days.

FIG. 21 shows no change of the X-ray powder diffraction (XRPD) of newpolymorphic form #4 combined with clozapine (300 mg) under high humidityconditions (of over 90% relative humidity) for 5 days.

FIG. 22 shows the X-ray powder diffraction (XRPD) of new polymorphicform #4, sodium benzoate (NaBen) from Merck, and sodium benzoate (NaBen)from Sigma Aldrich.

FIG. 23 shows the changes of X-ray powder diffraction (XRPD) of sodiumbenzoate (NaBen) from Merck combined with clozapine (100 mg) under highhumidity conditions (>90% RH, room temperature) for 8 days.

FIG. 24 shows no change of the X-ray powder diffraction (XRPD) ofpolymorphic form #4 of sodium benzoate combined with clozapine (100 mg)under high humidity conditions (>90% RH, room temperature) for 8 days.

FIG. 25 shows the X-ray powder diffraction (XRPD) of polymorphic form #1of sodium benzoate from Example 1, with peaks (°) of: 3.6, 4.2, 5.9,6.8, 7.5, 8.5, 9.2, 11.1, 11.7, 12.4, 14.9, 15.9, 16.6, 17.6, 18.8,19.4, 20.4, 21.6, 22.9, 23.7, 24.7, 25.1, 25.8, 26.1, 26.6, 27.7, 28.1,29.1, 29.4, 29.7, 30.2, 30.6, 30.9, 31.5, 32.4, 32.9, 33.6, 34.2, 35.7,38.6, and 39.6; wherein the X-ray diffraction pattern is determined by aperiod of a scan speed of about 1.0 second per step.

FIG. 26 shows the X-ray powder diffraction (XRPD) of polymorphic form #2of sodium benzoate from Example 2, with peaks (°) of: 3.7, 5.9, 6.8,7.5, 8.9, 11.1, 14.9, 17.6, 22.7, 23.5, 24.8, 26.2, 26.6, 27.6, 28.3,29.3, 30.2, 30.9, 32.2, 32.9, 34.0, 35.7, and 37.8; wherein the X-raydiffraction pattern is determined by a period of a scan speed of about1.0 second per step.

FIG. 27 shows the X-ray powder diffraction (XRPD) of polymorphic form #3of sodium benzoate from Example 3, with peaks (°) of: 3.7, 5.9, 6.3,6.8, 7.5, 9.4, 11.7, 16.4, 17.7, 23.6, 24.5, 25.7, 26.7, 27.7, 28.4,29.0, 29.4, 30.2, 30.4, 31.0, 31.2, 32.3, 34.2, 35.4, and 35.9; whereinthe X-ray diffraction pattern is determined by a period of a scan speedof about 1.0 second per step.

FIG. 28 shows the X-ray powder diffraction (XRPD) of polymorphic form #6of sodium benzoate from Example 6, with peaks (°) of: 3.7, 4.2, 5.6,5.9, 6.6, 7.4, 8.4, 9.4, 11.2, 12.5, 14.8, 17.6, 18.6, 21.6, 22.8, 23.6,25.1, 26.3, 26.5, 27.1, 28.2, 29.5, 30.2, 31.1, 31.3, 32.0, 33.0, 34.0,35.7, and 38.0; wherein the X-ray diffraction pattern is determined by aperiod of a scan speed of about 1.0 second per step.

FIG. 29 shows the X-ray powder diffraction (XRPD) of a sodium benzoatepolymorph was prepared following the conditions disclosed in Howard etal. (Crystal Growth and Design, Vol. 9, pages 3964-3975; see, e.g.,Section 2.4 and FIG. 4), with peaks (°) of: 4.2, 5.8, 6.8, 8.5, 10.0,11.7, 12.8, 14.8, 15.7, 16.4, 17.6, 18.7, 19.4, 20.4, 21.2, 22.5, 23.6,25.0, 25.9, 28.1, 29.0, 29.7, 30.2, 31.1, 32.4, 33.0, 34.2, and 35.7;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step.

DETAILED DESCRIPTION

The present disclosure provides novel polymorphic forms of sodiumbenzoate. The polymorphic forms are more stable than the amorphous andthe known polymorphic forms and are useful in treating and/or reducingthe risk for various diseases and disorders, including neuropsychiatricdisorders, in a subject. Thus, also provided herein are methods ofpreparing the polymorphic forms, compositions, kits, and methods ofusing the polymorphic forms of sodium benzoate described herein fortreating and/or reducing the risk for any of the target diseasesdescribed herein.

Further, the present disclosure provides a pharmaceutical compositioncomprises an effective amount of a sodium benzoate compound and aneffective amount of clozapine. The crystalline sodium benzoate of theinvention (i.e. the polymorphic form of sodium benzoate) is more stablethan the amorphous and the other known polymorphic forms of sodiumbenzoate or their combinations. Additionally, the excipients comprisedin the pharmaceutical composition described herein improve the stabilityof the combination of the sodium benzoate compound and clozapine. Thepharmaceutical composition described herein is useful in preventing,treating and/or reducing the risk for various diseases and disorders,including neuropsychiatric disorders, in a subject. Thus, also providedherein is a method for preventing, treating and/or reducing the risk forany of the target diseases described herein by administering thepharmaceutical composition described herein.

Novel Polymorphic Forms of Sodium Benzoate

One aspect of the present disclosure relates to the polymorphic forms ofsodium benzoate as described herein. These polymorphic forms are usefulin treating and/or reducing the risk for neuropsychiatric disorders in asubject.

In one aspect, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern comprising characteristic peaks at areflection angle 2θ of approximately 5.9, 30.2, and 31.2 degrees. Insome embodiments, the X-ray diffraction pattern can be determined by aperiod of a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form of sodium benzoate has a X-ray powderdiffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 3.6, 7.2, 7.5, 14.9, 15.9, 16.6,17.6, 18.8, 20.4, 22.9, 23.7, 25.1, 25.8, 26.6, 28.1, 29.1, 29.4, 29.7,31.5, 32.9, 34.2, and 35.7 degrees. In some embodiments, the X-raydiffraction pattern can be determined by a period of a scan speed ofabout 0.1 to 0.3 seconds per step. In some embodiments, the polymorphicform has a X-ray powder diffraction pattern substantially as depicted inFIG. 1. In some embodiments, the X-ray diffraction pattern can bedetermined by a period of a scan speed of about 0.1 to 0.3 seconds perstep. In some embodiments, the polymorphic form has a TGA patternsubstantially as depicted in FIG. 2. In some embodiments, thepolymorphic form has a DSC pattern substantially as depicted in FIG. 3.In some embodiments, the polymorphic form has an X-ray powderdiffraction pattern substantially as depicted in FIG. 1, a TGA patternsubstantially as depicted in FIG. 2, and a DSC pattern substantially asdepicted in FIG. 3.

In one aspect, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern comprising characteristic peaks at areflection angle 2θ of approximately 3.6, 7.5, 26.6, and 29.4 degrees;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In one aspect, the polymorphicform of sodium benzoate has a X-ray powder diffraction pattern furthercomprising characteristic peaks at a reflection angle 2θ ofapproximately 5.9, 6.8, 17.6, 27.6, 30.2, 30.9, and 32.3 degrees;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In one aspect, the polymorphicform of sodium benzoate has a X-ray powder diffraction pattern furthercomprising characteristic peaks at a reflection angle 2θ ofapproximately 11.1, 14.9, 26.2, 32.9, and 35.7 degrees; wherein theX-ray diffraction pattern is determined by a period of a scan speed ofabout 1.0 second per step. In one aspect, the polymorphic form of sodiumbenzoate has a X-ray powder diffraction pattern further comprisingcharacteristic peaks at a reflection angle 2θ of approximately 12.4 and22.9 degrees; wherein the X-ray diffraction pattern is determined by aperiod of a scan speed of about 1.0 second per step.

In one aspect, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern comprising characteristic peaks at areflection angle 2θ of approximately 3.6, 7.5, 26.6, and 29.4 degrees;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In some embodiments, thepolymorphic form of sodium benzoate has a X-ray powder diffractionpattern at a reflection angle 2θ further comprising characteristic peaksat approximately 4.2, 8.5, 9.2, 11.1, 11.7, 12.4, 14.9, 15.9, 16.6,18.8, 19.4, 20.4, 21.6, 22.9, 23.7, 24.7, 25.1, 25.8, 26.1, 28.1, 29.1,29.7, 30.6, 31.5, 32.9, 33.6, 34.2, 35.7, 38.6, and 39.6 degrees;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In some embodiments, thepolymorphic form has a X-ray powder diffraction pattern substantially asdepicted in FIG. 25; wherein the X-ray diffraction pattern is determinedby a period of a scan speed of about 1.0 seconds per step. In someembodiments, the polymorphic form has a TGA pattern substantially asdepicted in FIG. 2. In some embodiments, the polymorphic form has a DSCpattern substantially as depicted in FIG. 3. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 25, a TGA pattern substantially as depicted in FIG.2, and a DSC pattern substantially as depicted in FIG. 3.

In some embodiments, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 3.7, 6.8, 7.5, 11.3, 11.6, 17.6,22.7, 23.5, 26.2, 27.6, 28.3, 29.3, 32.2, 32.9, 34.0, and 35.7 degrees.In some embodiments, the X-ray diffraction pattern can be determined bya period of a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form has an X-ray powder diffractionpattern substantially as depicted in FIG. 4. In some embodiments, theX-ray diffraction pattern can be determined by a period of a scan speedof about 0.1 to 0.3 seconds per step. In some embodiments, thepolymorphic form has a TGA pattern substantially as depicted in FIG. 5.In some embodiments, the polymorphic form has a DSC patternsubstantially as depicted in FIG. 6. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 4, a TGA pattern substantially as depicted in FIG.5, and a DSC pattern substantially as depicted in FIG. 6.

In some embodiments, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 8.9, 11.1, 14.9, 22.7, 23.5, 24.8,26.2, 28.3, 32.9, 34.0, 35.7, and 37.8 degrees; wherein the X-raydiffraction pattern is determined by a period of a scan speed of about1.0 second per step. In some embodiments, the polymorphic form has anX-ray powder diffraction pattern substantially as depicted in FIG. 26;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In some embodiments, thepolymorphic form has a TGA pattern substantially as depicted in FIG. 5.In some embodiments, the polymorphic form has a DSC patternsubstantially as depicted in FIG. 6. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 26, a TGA pattern substantially as depicted in FIG.5, and a DSC pattern substantially as depicted in FIG. 6.

In some embodiments, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 3.7, 6.3, 6.8, 7.5, 11.7, 17.7,23.6, 24.5, 26.5, 27.0, 27.7, 28.4, 29.0, 30.2, 31.0, 31.2, 32.3, 34.2,and 35.9 degrees. In some embodiments, the X-ray diffraction pattern canbe determined by a period of a scan speed of about 0.1 to 0.3 secondsper step. In some embodiments, the polymorphic form has an X-ray powderdiffraction pattern substantially as depicted in FIG. 7. In someembodiments, the X-ray diffraction pattern can be determined by a periodof a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form has a TGA pattern substantially asdepicted in FIG. 8. In some embodiments, the polymorphic form has a DSCpattern substantially as depicted in FIG. 9. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 7, a TGA pattern substantially as depicted in FIG.8, and a DSC pattern substantially as depicted in FIG. 9.

In some embodiments, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 6.3, 9.4, 11.7, 16.4, 23.6, 24.5,25.7, 28.4, 29.0, 30.4, 31.0, 31.2, 34.2, 35.4, and 35.9 degrees;wherein the X-ray diffraction pattern is determined by a period of ascan speed of about 1.0 second per step. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 27; wherein the X-ray diffraction pattern isdetermined by a period of a scan speed of about 1.0 second per step. Insome embodiments, the polymorphic form has a TGA pattern substantiallyas depicted in FIG. 8. In some embodiments, the polymorphic form has aDSC pattern substantially as depicted in FIG. 9. In some embodiments,the polymorphic form has an X-ray powder diffraction patternsubstantially as depicted in FIG. 27, a TGA pattern substantially asdepicted in FIG. 8, and a DSC pattern substantially as depicted in FIG.9.

In some embodiments, the polymorphic form of sodium benzoate has a X-raypowder diffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 4.3, 7.1, 8.6, 10.1, 10.7, 12.9,13.8, 14.4, 17.2, 17.7, 18.5, 21.5, 22.0, 22.6, 23.7, 25.1, 25.9, 26.2,26.9, 27.9, 28.2, 28.8, 29.1, 29.7, 33.2, 34.9, 35.8, 36.1, and 39.3degrees. In some embodiments, the X-ray diffraction pattern can bedetermined by a period of a scan speed of about 0.1 to 0.3 seconds perstep. In some embodiments, the polymorphic form has an X-ray powderdiffraction pattern substantially as depicted in FIG. 10. In someembodiments, the X-ray diffraction pattern can be determined by a periodof a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form has a TGA pattern substantially asdepicted in FIG. 11. In some embodiments, the polymorphic form has a DSCpattern substantially as depicted in FIG. 12. In some embodiments, thepolymorphic form has a X-ray powder diffraction pattern substantially asdepicted in FIG. 10, a TGA pattern substantially as depicted in FIG. 11,and a DSC pattern substantially as depicted in FIG. 12.

In another aspect, the polymorphic form of sodium benzoate which has anX-ray diffraction pattern comprising characteristic peaks at areflection angle 2θ of approximately 3.7, 5.9, and 26.6 degrees. In someembodiments, the X-ray diffraction pattern can be determined by a periodof a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form of sodium benzoate has an X-ray powderdiffraction pattern at a reflection angle 2θ further comprisingcharacteristic peaks at approximately 5.5, 6.7, 7.4, 12.5, 14.7, 16.5,17.7, 22.0, 23.6, 24.6, 25.8, 27.6, 28.4, 30.2, 31.1, 32.3, 34.3, and35.9 degrees. In some embodiments, the X-ray diffraction pattern can bedetermined by a period of a scan speed of about 0.1 to 0.3 seconds perstep. In some embodiments, the polymorphic form has an X-ray powderdiffraction pattern substantially as depicted in FIG. 13. In someembodiments, the X-ray diffraction pattern can be determined by a periodof a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form has a TGA pattern substantially asdepicted in FIG. 14. In some embodiments, the polymorphic form has a DSCpattern substantially as depicted in FIG. 15. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 13, a TGA pattern substantially as depicted in FIG.14, and a DSC pattern substantially as depicted in FIG. 15.

In some embodiments, the polymorphic form of sodium benzoate has anX-ray powder diffraction pattern at a reflection angle 2θ furthercomprising characteristic peaks at approximately 6.6, 7.4, 9.4, 11.2,12.5, 22.8, 25.1, 26.3, 28.2, 29.5, 30.2, 31.1, 31.2, 33.0, and 34.0degrees. In some embodiments, the X-ray diffraction pattern can bedetermined by a period of a scan speed of about 0.1 to 0.3 seconds perstep. In some embodiments, the polymorphic form has a X-ray powderdiffraction pattern substantially as depicted in FIG. 16. In someembodiments, the X-ray diffraction pattern can be determined by a periodof a scan speed of about 0.1 to 0.3 seconds per step. In someembodiments, the polymorphic form has a TGA pattern substantially asdepicted in FIG. 17. In some embodiments, the polymorphic form has a DSCpattern substantially as depicted in FIG. 18. In some embodiments, thepolymorphic form has an X-ray powder diffraction pattern substantiallyas depicted in FIG. 16, a TGA pattern substantially as depicted in FIG.17, and a DSC pattern substantially as depicted in FIG. 18.

In some embodiments, the polymorphic form of sodium benzoate has anX-ray powder diffraction pattern at a reflection angle 2θ furthercomprising characteristic peaks at approximately 4.2, 5.6, 5.9, 6.6,8.4, 9.4, 12.5, 17.6, 18.6, 21.6, 22.8, 23.6, 25.1, 27.1, 28.2, 30.2,31.1, 31.3, 32.0, 34.0, and 38.0 degrees; wherein the X-ray diffractionpattern is determined by a period of a scan speed of about 1.0 secondper step. In some embodiments, the polymorphic form has a X-ray powderdiffraction pattern substantially as depicted in FIG. 28; wherein theX-ray diffraction pattern is determined by a period of a scan speed ofabout 1.0 second per step. In some embodiments, the polymorphic form hasa TGA pattern substantially as depicted in FIG. 17. In some embodiments,the polymorphic form has a DSC pattern substantially as depicted in FIG.18. In some embodiments, the polymorphic form has an X-ray powderdiffraction pattern substantially as depicted in FIG. 28, a TGA patternsubstantially as depicted in FIG. 17, and a DSC pattern substantially asdepicted in FIG. 18.

In some embodiments, the polymorphic form of sodium benzoate is preparedby a process comprising (i) dissolving sodium benzoate in a polarsolvent, to form a slurry, and (ii) stirring the slurry forapproximately 10 minutes to approximately 6 days to produce thepolymorphic form of sodium benzoate, and (iii) filtering and collectingthe solid thus formed. In some embodiments, the process furthercomprises adding acetonitrile after the sodium benzoate is dissolved inthe solvent in step (i). In some embodiments, the process furthercomprises adding acetonitrile after the sodium benzoate is dissolved inmethanol. In some embodiments, in step (i) of the process, the solventcomprises methanol and the process further comprises adding acetonitrileafter the sodium benzoate is dissolved in the solvent in step (i). Insome embodiments, the polar solvent comprises methanol, acetonitrile, orisobutanol, or a combination thereof. In some embodiments, the polarsolvent comprises water. In some embodiments, the polar solvent does notcomprise water. In some embodiments, the polar solvent comprisesmethanol, acetonitrile, or isobutanol, or a combination thereof, and nowater.

In some embodiments, in step (i), the solvent comprises methanol. Insome embodiments, the sodium benzoate is dissolved in methanol in step(i) and wherein in step (ii) the stirring of the slurry is forapproximately 10 minutes, or for approximately 2 days to approximately 6days. In some embodiments, the sodium benzoate is dissolved in methanolin step (i) and wherein in step (ii) the stirring of the slurry is forapproximately 10 minutes, or for approximately 2 days to approximately 4days. In some embodiments, the sodium benzoate is dissolved in methanolin step (i) and wherein in step (ii) the stirring of the slurry is forapproximately 10 minutes. In some embodiments, in step (i), the solventcomprises acetonitrile. In some embodiments, the sodium benzoate isdissolved in acetonitrile in step (i) and wherein in step (ii) thestirring of the slurry is for approximately 2 days. In some embodiments,the sodium benzoate is dissolved in acetonitrile in step (i) and whereinin step (ii) the stirring of the slurry is for approximately 2 days toapproximately 4 days. In some embodiments, in step (i), the solventcomprises isobutanol. In some embodiments, the sodium benzoate isdissolved in isobutanol in step (i) and wherein in step (ii) thestirring of the slurry is for approximately 2 days to approximately 6days. In some embodiments, the sodium benzoate is dissolved inisobutanol in step (i) and wherein in step (ii) the stirring of theslurry is for approximately 4 days to approximately 6 days. In someembodiments, the sodium benzoate is dissolved in isobutanol in step (i)and wherein in step (ii) the stirring of the slurry is for approximately6 days. In some embodiments, wherein the sodium benzoate is dissolved inmethanol in step (i), wherein step (ii) comprises further adding theacetonitrile after the sodium benzoate is dissolved in methanol, andwherein in step (ii) the stirring of the slurry is for approximately 2days. In some embodiments, wherein the sodium benzoate is dissolved inmethanol in step (i), wherein step (ii) comprises further adding theacetonitrile after the sodium benzoate is dissolved in methanol, andwherein in step (ii) the stirring of the slurry is for approximately 2days to approximately 6 days. In some embodiments, in the process, thesodium benzoate is dissolved in methanol in step (i), the processfurther comprises adding acetonitrile after the sodium benzoate isdissolved in methanol in step (i), and wherein in step (ii) the stirringof the slurry is for approximately 2 days to approximately 4 days.

Any of the polymorphic forms of sodium benzoate described herein has achemical purity of about 95%, 97%, 98%, 99%, 99.5%, 99.9% or higher,which can be determined by a conventional method, for example, HPLC or¹H Nuclear Magnetic Resonance (¹H-NMR) spectroscopy. In someembodiments, the polymorphic form of sodium benzoate described hereincontains less than 10%, preferably less than 5%, preferably less than1%, preferably less than 0.5%, and most preferably less than 0.1% ofsodium benzoate in other polymorphic or amorphous forms (as measured byXRPD or DSC).

Compositions

The present disclosure provides a pharmaceutical composition comprisingan effective amount of a sodium benzoate compound and an effectiveamount of clozapine. In certain embodiments, the pharmaceuticalcomposition comprises 50 to 1000 mg of sodium benzoate compound (e.g.,100 to 800 mg, 200 to 600 mg, or 300 to 500 mg) and 25 to 300 mg ofclozapine (e.g., 50 to 250 mg, 100 to 200 mg, or 150-300 mg). In certainembodiments, the pharmaceutical composition comprises 500 mg of sodiumbenzoate compound and 200 to 300 mg of clozapine.

In some embodiments, the sodium benzoate compound (e.g., sodiumbenzoate) can be in amorphous form, or in one or more polymorphic forms.In some examples, the sodium benzoate can be mixture of amorphous formand one or more polymorphic forms. In one example, the sodium benzoatecompound can be a commercially available sodium benzoate, which mayinclude amorphous and a variety of polymorphic forms of sodium benzoate(e.g. purchased from Merck, Formosa, Sigma Aldrich, and the like), andthe purified polymorphic form of sodium benzoate of the invention. Insome embodiments, the sodium benzoate compound comprises a polymorphicform of sodium benzoate as described herein.

The present disclosure also provides compositions comprising apolymorphic form of sodium benzoate described herein, and a carrier,excipient, diluent, binder, additive, filler, and lubricant, or amixture thereof. In certain embodiments, the composition comprises apolymorphic form of sodium benzoate described herein and apharmaceutically acceptable carrier. In certain embodiments, thecomposition comprises a polymorphic form of sodium benzoate describedherein and a pharmaceutically acceptable excipient. In certainembodiments, the composition comprises a polymorphic form of sodiumbenzoate described herein and a pharmaceutically acceptable diluent. Incertain embodiments, the composition comprises a polymorphic form ofsodium benzoate described herein and a pharmaceutically acceptablebinder. In certain embodiments, the composition comprises a polymorphicform of sodium benzoate described herein and a pharmaceuticallyacceptable additive. In certain embodiments, the composition comprises apolymorphic form of sodium benzoate described herein and apharmaceutically acceptable filler. In certain embodiments, thecomposition comprises a polymorphic form of sodium benzoate describedherein and a pharmaceutically acceptable lubricant.

In certain embodiments, the pharmaceutical composition described hereinfurther comprises one or more pharmaceutically acceptable excipients. Incertain embodiments, the pharmaceutical composition comprises 50 to 1000mg of sodium benzoate compound, 25 to 300 mg of clozapine, and one ormore pharmaceutically acceptable excipients. In certain embodiments, thepharmaceutical composition comprises 500 mg of sodium benzoate compound,200 to 300 mg of clozapine, and one or more pharmaceutically acceptableexcipients.

In certain embodiments, the ratio of the sodium benzoate compound toclozapine is about 1:10 to about 1000:1, about 1:10 to about 900:1,about 1:10 to about 800:1, about 1:10 to about 600:1, about 1:10 toabout 500:1, about 1:10 to about 400:1, about 1:10 to about 200:1, about1:10 to about 100:1, about 1:10 to about 75:1, about 1:10 to about 50:1,about 1:10 to about 25:1, about 1:10 to about 10:1, about 1:10 to about5:1, about 1:10 to about 1:2, about 1:10 to about 1:5, or about 1:10 toabout 1:8 by weight. In certain embodiments, the ratio of the sodiumbenzoate compound to clozapine is about 20:1, about 5:1, about 2.5:1, orabout 1.67:1 by weight.

In certain embodiments, the sodium benzoate compound described herein isprovided in an effective amount in the pharmaceutical composition. Incertain embodiments, clozapine is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the effective amountis a therapeutically effective amount (e.g., amount effective fortreating and/or reducing the risk for a neuropsychiatric disorder in asubject in need thereof). In certain embodiments, the effective amountis a prophylactically effective amount (e.g., amount effective forpreventing a neuropsychiatric disorder in a subject in need thereof).

In certain embodiments, the pharmaceutical composition disclosed hereincomprises 50 to 1000 mg of sodium benzoate (e.g., 100 to 800 mg, 200 to600 mg, or 300 to 500 mg), 25-300 mg of clozapine (e.g., 50 to 200 mg,100 to 150 mg, or 150 to 300 mg), 50-500 mg of sodium alginate (e.g.,100 to 400 mg, 200 to 300 mg, or 250 to 400 mg), 50-400 mg of sodiumcitrate (e.g., 100-300 mg, 150-250 mg, or 200-300 mg), 5-100 mg ofmagnesium stearate (e.g., 10-80 mg, 25-70 mg, 40-60 mg, or 50-100 mg),and 80-200 mg of sodium starch glycolate (e.g., 100-150 mg). In certainembodiments, the pharmaceutical composition disclosed herein comprises125 to 500 mg of sodium benzoate, 25-300 mg of clozapine, 50-500 mg ofsodium alginate, 50-400 mg of sodium citrate, 5-100 mg of magnesiumstearate, and 80-200 mg of sodium starch glycolate.

In certain embodiments, the pharmaceutical composition disclosed hereincomprises 50 to 1000 mg of sodium benzoate, 25-300 mg of clozapine,50-200 mg of sodium alginate, 50-400 mg of sodium citrate, 5-100 mg ofmagnesium stearate, and 80-200 mg of sodium starch glycolate. In certainembodiments, the pharmaceutical composition disclosed herein comprises125 to 500 mg of sodium benzoate, 25-300 mg of clozapine, 50-200 mg ofsodium alginate, 50-400 mg of sodium citrate, 5-100 mg of magnesiumstearate, and 80-200 mg of sodium starch glycolate.

In certain embodiments, the pharmaceutical composition disclosed hereincomprises 50 to 1000 mg of sodium benzoate, 25-300 mg of clozapine,50-70 mg of sodium alginate, 50-70 mg of sodium citrate, 5-15 mg ofmagnesium stearate, and 80-100 mg of sodium starch glycolate. In certainembodiments, the pharmaceutical composition disclosed herein comprises125 to 500 mg of sodium benzoate, 25-300 mg of clozapine, 50-70 mg ofsodium alginate, 50-70 mg of sodium citrate, 5-15 mg of magnesiumstearate, and 80-100 mg of sodium starch glycolate.

In certain embodiments, the composition further comprises aneuropharmaceutical. In certain embodiments, the neuropharmaceutical isselected from the group consisting of butyrophenone, phenothiazine,fluphenazine, perphenazine, prochlorperazine, thioridazine,trifluoperazine, mesoridazine, promazine, triflupromazine,levomepromazine, promethazine, thioxanthene, chlorprothixene,flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine,risperidone, quetiapine, ziprasidone, amisulpride, asenapine,paliperidone, aripiprazole, cariprazine, brexpiprazole, lamotrigine,tetrabenazine, cannabidiol, LY2140023, droperidol, pimozide,butaperazine, carphenazine, eemoxipride, piperacetazine, sulpiride,acamprosate, tetrabenazine, vilazodone, levomilnacipran, andvortioxetine, fluoxetine, paroxetine, escitalopram, citalopram,sertraline, fluvoxamine, venlafaxine, milnacipram, duloxetine,mirtazapine, mianserin, reboxetine, bupropion, amitriptyline,nortriptiline, protriptyline, desipramine, trimipramine, amoxapine,clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine,trazodone, nefazodone, lamatrogine, lithium, topiramate, gabapentin,carbamazepine, oxacarbazepine, valporate, maprotiline, mirtazapine,brofaromine, gepirone, moclobemide, isoniazid, iproniazid, phenelzine,selegiline, a statin, an amphetamine, modafinil, desoxyn,methamphetamine, cocaine, arecoline, dexmethylphenidate,dextroamphetamine, methylphenidate, lisdexamfetamine dimesylate, mixedsalts amphetamine, atomoxetine, clonidine hydrochloride, guanfacinehydrochloride, arecoline, pemoline, donepezil, tacrine, rivastigmine,memantine, physostigmine, lithium salts, nicotine, arecoline, huperzinealpha, riluzole, sarcosine, vitamin C, vitamin E, carotenoids, tannicacid, and Ginkgo biloba extract. The compositions described herein areuseful in treating and/or reducing the risk for a neuropsychiatricdisorder. In certain embodiments, the ratio of the polymorphic form ofsodium benzoate to the neuropharmaceutical is about 1:10 to about1000:1, about 1:10 to about 900:1, about 1:10 to about 800:1, about 1:10to about 600:1, about 1:10 to about 500:1, about 1:10 to about 400:1,about 1:10 to about 200:1, about 1:10 to about 100:1, about 1:10 toabout 75:1, about 1:10 to about 50:1, about 1:10 to about 25:1, about1:10 to about 10:1, about 1:10 to about 5:1, about 1:10 to about 1:2,about 1:10 to about 1:5, or about 1:10 to about 1:8 by weight.

In certain embodiments, the composition is a pharmaceutical composition.In certain embodiments, the composition is a nutraceutical composition.In certain embodiments, the composition is a health food. In someembodiments, the compositions described herein can be a health food orhealth food product, which can be any kinds of liquid andsolid/semi-solid materials that are used for nourishing humans andanimals, for improving basic behavioral functioning, hyperactivity,mood, anxiety, depression, perception, sensorimotor gating, painthreshold, memory and/or cognitive functioning, or for facilitatingtreatment of any of the target diseases noted herein (e.g., aneuropsychiatric disorder, including those described herein). The healthfood product may be a food product (e.g., tea-based beverages, juice,soft drinks, coffee, milk, jelly, cookies, cereals, chocolates, snackbars, herbal extracts, dairy products (e.g., ice cream, and yogurt)), afood/dietary supplement, or a nutraceutical formulation.

The health food product described herein, may comprise one or moreedible carriers, which confer one or more of the benefits to the productas described herein. Examples of edible carriers include starch,cyclodextrin, maltodextrin, methylcellulose, carbonmethoxy cellulose,xanthan gum, and aqueous solutions thereof. Other examples includesolvents, dispersion media, coatings, surfactants, antioxidants,preservatives (e.g., antibacterial agents, antifungal agents), isotonicagents, absorption delaying agents, stabilizers, gels, binders,excipients, disintegration agents, lubricants, sweetening agents,flavoring agents, dyes, such like materials and combinations thereof, aswould be known to one of ordinary skill in the art. In some examples,the health food products described herein may further includeneuroprotective foods, such as fish oil, flax seed oil, and/or benzoate.

In some examples, the health food product is a nutraceuticalcomposition, which refers to compositions containing components fromfood sources and conferring extra health benefits in addition to thebasic nutritional value found in foods. A nutraceutical composition asdescribed herein comprises the polymorphic form described herein (e.g.,the sodium benzoate compound and polymorphic form as described herein)and additional ingredients and supplements that promote good healthand/or enhance stability and bioactivity of the polymorphic forms.

The actions of nutraceutical compositions may be fast or/and short-termor may help achieve long-term health objectives as those describedherein, e.g., improving basic behavioral functioning, hyperactivity,mood, anxiety, depression, perception, sensorimotor gating, painthreshold, memory and/or cognitive functioning in, e.g., human subjectswho have or are at risk for a neuropsychiatric disorder. Thenutraceutical compositions may be contained in an edible material, forexample, as a dietary supplement or a pharmaceutical formulation. As adietary supplement, additional nutrients, such as vitamins, minerals oramino acids may be included. The composition can also be a drink or afood product, e.g., tea, soft drink, juice, milk, coffee, cookie,cereal, chocolate, and snack bar. If desired, the composition can besweetened by adding a sweetener such as sorbitol, maltitol, hydrogenatedglucose syrup and hydrogenated starch hydrolyzate, high fructose cornsyrup, cane sugar, beet sugar, pectin, or sucralose.

The nutraceutical composition disclosed herein can be in the form of asolution. For example, the nutraceutical formulation can be provided ina medium, such as a buffer, a solvent, a diluent, an inert carrier, anoil, or a creme. In some examples, the formulation is present in anaqueous solution that optionally contains a non-aqueous co-solvent, suchas an alcohol. The nutraceutical composition can also be in the form ofpowder, paste, jelly, capsule, or tablet. Lactose and corn starch arecommonly used as diluents for capsules and as carriers for tablets.Lubricating agents, such as magnesium stearate, are typically added toform tablets.

The health food products may be formulated for a suitable administrationroute, for example, oral administration. For oral administration, thecomposition can take the form of, for example, tablets or capsules,prepared by conventional means with acceptable excipients such asbinding agents (for example, pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (forexample, lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (for example, magnesium stearate, talc orsilica); disintegrants (for example, potato starch or sodium starchglycolate); or wetting agents (for example, sodium lauryl sulphate). Thetablets can be coated by methods well known in the art. Also includedare bars and other chewable formulations.

In some examples, the health food product can be in a liquid form andthe one or more edible carriers can be a solvent or dispersion mediumcomprising but not limited to, ethanol, polyol (e.g., glycerol,propylene glycol, liquid polyethylene glycol), lipids (e.g.,triglycerides, vegetable oils, liposomes) or combinations thereof. Theproper fluidity can be maintained, for example, by the use of a coating,such as lecithin; by the maintenance of the required particle size bydispersion in carriers such as, for example liquid polyol or lipids; bythe use of surfactants such as, for example hydroxypropylcellulose; orcombinations thereof. In many cases, it will be advisable to include anisotonic agent, such as, for example, sugars, sodium chloride orcombinations thereof.

Liquid preparations for oral administration can take the form of, forexample, solutions, syrups or suspensions, or they can be presented as adry product for constitution with water or other suitable vehicle beforeuse. In one embodiment, the liquid preparations can be formulated foradministration with fruit juice. Such liquid preparations can beprepared by conventional means with pharmaceutically acceptableadditives such as suspending agents (for example, sorbitol syrup,cellulose derivatives or hydrogenated edible fats); emulsifying agents(for example, lecithin or acacia); non-aqueous vehicles (for example,almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (for example, methyl or propyl-p-hydroxybenzoates,benzoate or sorbate).

In certain embodiments, the composition is a medical food. A medicalfood product is a food product formulated to be consumed or administeredenterally. Such a food product is usually used under the supervision ofa physician for the specific dietary management of a target disease,such as those described herein. In some instances, such a medical foodcomposition is specially formulated and processed (as opposed to anaturally occurring foodstuff used in a natural state) for a patient inneed of the treatment (e.g., human patients who suffer from illness orwho requires use of the product as a major active agent for alleviatinga disease or condition via specific dietary management). In someexamples, a medical food composition described herein is not one ofthose that would be simply recommended by a physician as part of anoverall diet to manage the symptoms or reduce the risk of a disease orcondition.

Any of the medical food compositions described herein, comprising apolymorphic form of sodium benzoate and at least one carrier (e.g.,those described herein), can be in the form of a liquid solution;powder, bar, wafer, a suspension in an appropriate liquid or in asuitable emulsion, as detailed below. The at least one carrier, whichcan be either naturally-occurring or synthetic (non-naturallyoccurring), would confer one or more benefits to the sodium benzoate andco-former in the composition, for example, stability, bioavailability,and/or bioactivity. Any of the carriers described herein may be used formaking the medical food composition. In some embodiments, the medicalfood composition may further comprise one or more additional ingredientsselected from the group including, but not limited to natural flavors,artificial flavors, major trace and ultra-trace minerals, minerals,vitamins, oats, nuts, spices, milk, egg, salt, flour, lecithin, xanthangum and/or sweetening agents. The medical food composition may be placedin a suitable container, which may further comprise at least anadditional therapeutic agent such as those described herein.

In certain embodiments, the polymorph described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount(e.g., amount effective for treating and/or reducing the risk for aneuropsychiatric disorder in a subject in need thereof). In certainembodiments, the neuropsychiatric disorder is a neurological disorder,e.g., Alzheimer's disease. In certain embodiments, the effective amountis a prophylactically effective amount (e.g., amount effective forpreventing a neuropsychiatric disorder in a subject in need thereof).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the polymorphic form of sodium benzoatedescribed herein (i.e., the “active ingredient”) into association with acarrier or excipient, and/or one or more other accessory ingredients,and then, if necessary and/or desirable, shaping, and/or packaging theproduct into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, sodium starch glycolate (SSG),croscarmellose, crospovidone, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as colloidal silicondioxide, talc, calcium stearate, magnesium stearate, solid polyethyleneglycols, sodium lauryl sulfate, and mixtures thereof. In the case ofcapsules, tablets, and pills, the dosage form may include a bufferingagent such as sodium citrate, and chitosan. In addition, thepharmaceutically acceptable excipient described herein can be singlespecies or a mixture of multiple species of tannic acid, or apharmaceutically acceptable salt thereof.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the digestive tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the digestive tract, optionally, ina delayed manner. Examples of encapsulating agents which can be usedinclude, but are not limited to, polymeric substances and waxes.

Although the descriptions of pharmaceutical compositions provided hereinare mainly directed to pharmaceutical compositions which are suitablefor administration to humans, such compositions are generally suitablefor administration to animals of all sorts. Modification ofpharmaceutical compositions suitable for administration to humans inorder to render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

The polymorphic forms provided herein are typically formulated in dosageunit form for ease of administration and uniformity of dosage. It willbe understood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orpolymorphic form of sodium benzoate described herein and a container(e.g., a vial, ampule, bottle, syringe, and/or dispenser package, orother suitable container). In some embodiments, provided kits mayoptionally further include a second container comprising apharmaceutical excipient for dilution or suspension of a pharmaceuticalcomposition or polymorphic form of sodium benzoate described herein. Insome embodiments, the pharmaceutical composition or polymorphic form ofsodium benzoate described herein provided in the first container and thesecond container are combined to form one unit dosage form.

In certain embodiments, a kit described herein includes a firstcontainer comprising a polymorphic form or composition described herein.In certain embodiments, a kit described herein is useful in treatingand/or reducing the risk for a neuropsychiatric disorder in a subject inneed thereof.

In certain embodiments, a kit described herein further includesinstructions for using the polymorphic form or composition included inthe kit. A kit described herein may also include information as requiredby a regulatory agency such as the U.S. Food and Drug Administration(FDA). In certain embodiments, the information included in the kits isprescribing information. In certain embodiments, the kits andinstructions provide for treating and/or reducing the risk for aneuropsychiatric disorder in a subject in need thereof. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Method of Synthesis

Described herein are a number of exemplary methods for preparing thepolymorphic forms of sodium benzoate described herein:

General Method 1: Crystallization Via Evaporation in Saturated Solution.

Crystallization was carried out by evaporation in a saturated solution.Excess amount of sodium benzoate was dissolved in a solvent. Thesolution was filtered and the filtrate was evaporated to dryness toafford a new polymorphic form of sodium benzoate.

In one aspect, the synthesis of a polymorphic form of sodium benzoateincludes a first step of dissolving an excess amount of sodium benzoatein a single or mixed suitable solvent to form a saturated solution atambient pressure and temperature. The saturated solution may then befiltrated using a filter having a pore size ranging from 5 to 100 m toremove insoluble components. The solution thus obtained can beevaporated for a suitable period of time under suitable conditions toallow for formation of a polymorphic form of sodium benzoate (e.g.,polymorphic form No. 1 as described in Example 1 below). In certainembodiments, the solution is evaporated at ambient or reduced pressureand/or at an elevated temperature, e.g., approximately 40-110° C. Incertain embodiments, the elevated temperature can range fromapproximately 40-90° C., approximately 40-80° C., approximately 40-70°C., or approximately 40-60° C. The polymorphic form of sodium benzoateformed from the evaporated solution can then be collected.

Suitable solvents for use in the synthesis methods described hereininclude, but are not limited to, polar protic solvents (e.g., methanol,ethanol, isopropanol, water), polar aprotic solvents (e.g.,acetonitrile, ethyl acetate), or a mixture thereof. In certainembodiments, the solvent is methanol, ethanol, isopropanol,acetonitrile, ethyl acetate, water, or mixtures thereof.

A polar solvent refers to a solvent having a large dipole moment (e.g,approximately 1.6 D and higher). For example, polar solvents include,but are not limited to, methanol, ethanol, isobutanol, n-butanol,isopropanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), water,acetonitrile, ethyl acetate, pyridine, or acetone.

General Method 2: Crystallization Via Cooling in Saturation Solution.

To sodium benzoate was added a single or mixed solvent at elevatedtemperature (50-110° C.) while stirring. The addition of solvent washalted immediately when the solution became clear. The solution wasallowed to cool down while stirring. The suspension was filtered and thecrystals were harvested to afford a new polymorphic form of sodiumbenzoate.

For example, the synthesis of a polymorphic form of sodium benzoateincludes a first step of dissolving sodium benzoate in a single or mixedsuitable solvent at a temperature ranging from about 50-110° C. to forma solution. Suitable solvents for use in the synthesis methods describedherein include, but are not limited to, polar protic solvents (e.g.,methanol, ethanol, isopropanol, water), polar aprotic solvents (e.g.,acetonitrile, ethyl acetate), or a mixture thereof. In certainembodiments, the solvent is methanol, ethanol, isopropanol,acetonitrile, ethyl acetate, water, or mixtures thereof. In certainembodiments, the synthesis of a polymorphic form of sodium benzoateincludes a first step of dissolving sodium benzoate in a single or mixedsolvent at a temperature of 50-110° C., 50-100° C., 50-90° C., 50-80°C., 50-70° C., or 60-70° C. to form a solution. In certain embodiments,the synthesis of a polymorphic form of sodium benzoate includes a firststep of dissolving sodium benzoate in a single or mixed solvent at atemperature of 50° C., 60° C., 70° C., 80° C., 90° C., 100° C., or 110°C. to form a solution.

In certain embodiments, the heated solution of dissolved sodium benzoateis then cooled to ambient temperature (e.g., about 20 to 25° C.) whilestirring. In certain embodiments, the cooled solution is then placed atambient temperature to allow formation of a polymorphic form of sodiumbenzoate. In certain embodiments, the polymorphic form of sodiumbenzoate formed by placement at ambient temperature in the third step iscollected. In certain embodiments, the polymorphic form of sodiumbenzoate formed by placement at ambient temperature is collected byfiltration using a filter having a pore size ranging from 5 to 100 μm.

General Method 3: Transformation in High Humidity Conditions

Sodium benzoate was stored in conditions with greater than 90% RH(relative humidity) to afford a new polymorphic form of sodium benzoate.

For example, the synthesis of a polymorphic form of sodium benzoateincludes a first step of placing sodium benzoate at a relative humidity(RH) greater than about 90% for about 1 to 10 days, during which apolymorphic form of sodium benzoate forms. In certain embodiments, thefirst step includes placing sodium benzoate at a RH of about 90%, about91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%,about 98%, about 99%, or about 100%. In certain embodiments, the firststep includes placing sodium benzoate at a relative humidity (RH)greater than about 90% for about 1 to 10 days, about 1 to 9 days, about1 to 8 days, about 1 to 7 days, about 1 to 6 days, about 1 to 5 days,about 1 to 4 days, about 1 to 3 days, or about 1 to 2 days. Thepolymorphic form of sodium benzoate formed in the first step may then becollected.

General Method 4: Transformation in Slurry Solution

The slurry solution of sodium benzoate in a solvent was mixed for acertain period of time to afford a new polymorphic form of sodiumbenzoate.

For example, the synthesis of a polymorphic form of sodium benzoateincludes a first step of preparing a slurry of a first polymorphic formof sodium benzoate in a single or mixed solvent. Suitable solvents foruse in the synthesis methods described herein include, but are notlimited to, polar protic solvents (e.g., methanol, ethanol, isopropanol,butanol, isobutanol, methyl-1-butanol, or water), polar aprotic solvents(e.g., acetonitrile, ethyl acetate, dioxane, methyl ethyl ketone, methylt-butyl ether, toluene, or tetrahydrofuran), or a mixture thereof. Incertain embodiments, the solvent is methanol, ethanol, isopropanol,butanol, acetonitrile, ethyl acetate, methyl ethyl ketone,tetrahydrofunan, water, or mixtures thereof. In certain embodiments, thesynthesis of a polymorphic form of sodium benzoate includes a secondstep of stirring the slurry for 6 hours to 10 days, 6 hours to 9 days, 6hours to 8 days, 6 hours to 7 days, 6 hours to 6 days, 6 hours to 5days, 6 hours to 4 days, 6 hours to 3 days, 6 hours to 2 days, 6 hoursto 1 day, 6 hours to 20 hours, 6 hours to 15 hours, 6 hours to 10 hours,or 6 hours to 8 hours, during which a polymorphic form of sodiumbenzoate forms. In certain embodiments, in the second step, the slurryis stirred for 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours,14 hours, 15 hours, 18 hours, 20 hours, 22 hours, 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 8 days, or 9 days. In certainembodiments, the synthesis of a polymorphic form of sodium benzoateincludes a third step of collecting the polymorphic form of sodiumbenzoate formed in the second step. The polymorphic form of sodiumbenzoate may be collected by filtration using a filter having a poresize ranging from 5 to 100 μm.

General Method 5: Crystallization Via Precipitation by Anti-Solvent

Sodium benzoate was fully dissolved in a solvent, followed by thegradual addition of an anti-solvent. The slurry was stirred for acertain period of time and the crystals were harvested to afford a newpolymorphic form of sodium benzoate.

For example, the synthesis of a polymorphic form of sodium benzoateincludes a first step of dissolving sodium benzoate in a single or mixedsolvent to form a solution. Suitable solvents for use in the synthesismethods described herein include, but are not limited to, polar proticsolvents (e.g., methanol, ethanol, isopropanol, water), polar aproticsolvents (e.g., acetonitrile, ethyl acetate), or a mixture thereof. Incertain embodiments, the solvent is methanol, ethanol, isopropanol,acetonitrile, ethyl acetate, water, or mixtures thereof. The solution ofdissolved sodium benzoate may then be mixed with an anti-solvent to forma slurry, wherein the volume ratio between the anti-solvent and thesolution in the first step is about 4:1 to 15:1. Suitable solvents foruse in the synthesis methods described herein include, but are notlimited to, polar protic solvents (e.g., methanol, ethanol, isopropanol,butanol, water), polar aprotic solvents (e.g., acetonitrile, acetone,ethyl acetate, tetrahydrofuran, methyl ethyl ketone), nonpolar solvents(toluene, tetrahydrofuran, methyl t-butyl ether), or a mixture thereof.In certain embodiments, the anti-solvent is acetone, acetonitrile,butanol, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate,isobutanol, isopropanol, methyl ethyl ketone, methyl-1-butanol, methylt-butyl ether, tetrahydrofuran, toluene, or mixtures thereof. In certainembodiments, in the second step of mixing dissolved sodium benzoatesolution with anti-solvent to form a slurry, the volume ratio betweenthe anti-solvent and the solution in the first step is about 4:1 to15:1, about 4:1 to 13:1, about 4:1 to 11:1, about 4:1 to 9:1, about 4:1to 7:1, or about 4:1 to 5:1. In certain embodiments, in the second step,the volume ratio between the anti-solvent and the solution in the firststep is about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about9:1, or about 10:1.

In certain embodiments, the slurry may be then stirred at ambientpressure and temperature for about 2-10 days, during which a polymorphicform of sodium benzoate forms. In certain embodiments, the slurry isstirred at ambient pressure and temperature for about 2-8 days, about2-7 days, about 2-6 days, about 2-5 days, about 2-4 days, or about 2-3days. In certain embodiments, the slurry is stirred at ambient pressureand temperature for about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 8 days, about 9 days, or about10 days. The polymorphic form of sodium benzoate formed in the thirdstep by stirring the slurry of sodium benzoate solution is thencollected. In certain embodiments, the polymorphic form of sodiumbenzoate is collected by filtration using a filter having a pore sizeranging from 5 to 100 am.

Alternatively, the synthesis of a polymorphic form of sodium benzoateincludes a first step of preparing a slurry of the polymorphic form ofsodium benzoate in a single or mixed solvent in the presence of about2-10% of water by volume. Suitable solvents for use in the synthesismethods described herein include, but are not limited to, polar proticsolvents (e.g., methanol, ethanol, isopropanol, or butanol), polaraprotic solvents (e.g., acetonitrile, ethyl acetate, dioxane, methylethyl ketone, methyl t-butyl ether, toluene, or tetrahydrofuran), or amixture thereof. In certain embodiments, the solvent is methanol,ethanol, isopropanol, acetonitrile, ethyl acetate, or mixtures thereof.In certain embodiments, the first step comprises preparing a slurry ofthe polymorphic form of sodium benzoate in the presence of less thanabout 10%, less than about 9%, less than about 8%, less than about 7%,less than about 6%, less than about 5%, less than about 4%, less thanabout 3%, or less than about 2%, of water by volume. In certainembodiments, the synthesis of a polymorphic form of sodium benzoateincludes a second step of stirring the slurry at ambient pressure andtemperature for about 2 to 10 days, during which a polymorphic form ofsodium benzoate forms. In certain embodiments, the second step comprisesstirring the slurry at ambient pressure and temperature for about 2 to10 days, about 2-8 days, about 2-7 days, about 2-6 days, about 2-5 days,about 2-4 days, or about 2-3 days. In certain embodiments, the secondstep comprises stirring the slurry at ambient pressure and temperaturefor about 2 days, about 3 days, about 4 days, about 5 days, about 6days, about 7 days, about 8 days, about 9 days, or about 10 days. Incertain embodiments, the synthesis of a polymorphic form of sodiumbenzoate includes a third step of collecting the polymorphic form ofsodium benzoate formed by stirring the slurry of sodium benzoate. Incertain embodiments, the polymorphic form of sodium benzoate iscollected by filtration using a filter having a pore size ranging from 5to 100 μm.

Exemplary methods for preparing the polymorphic forms of sodium benzoatedescribed herein are provided in the Examples below.

Methods of Treatment

The present disclosure provides methods of treating and/or reducing therisk for a neuropsychiatric disorder, in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., therapeutically effective amount) of a polymorph, or any of thecompositions described herein (e.g., comprising a polymorph of sodiumbenzoate or a combination of sodium benzoate and clozapine).

Another aspect of the present disclosure relates to methods ofpreventing a neuropsychiatric disorder in a subject in need thereof, themethods comprising administering to the subject an effective amount(e.g., prophylactically effective amount) of a polymorph, or compositionthereof, described herein.

The polymorphic forms and compositions described herein are useful intreating and/or preventing neuropsychiatric disorders. In certainembodiments, the neuropsychiatric disorder is schizophrenia. In certainembodiments, the neuropsychiatric disorder is a psychotic disorder. Incertain embodiments, the neuropsychiatric disorder is Alzheimer'sdisease. In certain embodiments, the neuropsychiatric disorder isdementia including frontotemporal dementia. In certain embodiments, theneuropsychiatric disorder is mild cognitive impairment. In certainembodiments, the neuropsychiatric disorder is benign forgetfulness. Incertain embodiments, the neuropsychiatric disorder is closed headinjury. In certain embodiments, the neuropsychiatric disorder isautistic spectrum disorder including Asperger's disorder. In certainembodiments, the neuropsychiatric disorder is an attention deficithyperactivity disorder. In certain embodiments, the neuropsychiatricdisorder is obsessive compulsive disorder. In certain embodiments, theneuropsychiatric disorder is a tic disorder. In certain embodiments, theneuropsychiatric disorder is a childhood learning disorder. In certainembodiments, the neuropsychiatric disorder is premenstrual syndrome. Incertain embodiments, the neuropsychiatric disorder is depression,including dysthymia and bereavement. In certain embodiments, theneuropsychiatric disorder is bipolar disorder including bipolar I and IIdisorders. In certain embodiments, the neuropsychiatric disorder is ananxiety disorder including panic and phobic disorders. In certainembodiments, the neuropsychiatric disorder is post-traumatic stressdisorder. In certain embodiments, the neuropsychiatric disorder ischronic pain. In certain embodiments, the neuropsychiatric disorder isan eating disorder including bulimia and anorexia. In certainembodiments, the neuropsychiatric disorder is an addiction disorderincluding substance dependence or abuse. In certain embodiments, theneuropsychiatric disorder is a personality disorder. In certainembodiments, the neuropsychiatric disorder is Parkinson's disorder. Incertain embodiments, the neuropsychiatric disorder is Huntington'sdisorder. In certain embodiments, the neuropsychiatric disorder ismultiple sclerosis. In certain embodiments, the neuropsychiatricdisorder is amyotrophic lateral sclerosis.

In certain embodiments, the method described herein further includesadministering to the subject an additional pharmaceutical agent. Incertain embodiments, the method described herein further includescontacting the biological sample with an additional pharmaceuticalagent. In certain embodiments, the method described herein furtherincludes contacting the tissue with an additional pharmaceutical agent.In certain embodiments, the method described herein further includescontacting the cell with an additional pharmaceutical agent.

The polymorphic forms and compositions provided herein can beadministered by any route, including enteral (e.g., oral), parenteral,intravenous, intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, subcutaneous,intradermal, rectal, intravaginal, intraperitoneal, topical (as bypowders, ointments, creams, and/or drops). Specifically contemplatedroutes are oral administration, intravenous administration (e.g.,systemic intravenous injection), regional administration via bloodand/or lymph supply, and/or direct administration to an affected site.In general, the most appropriate route of administration will dependupon a variety of factors including the nature of the agent (e.g., itsstability in the environment of the gastrointestinal tract), and/or thecondition of the subject (e.g., whether the subject is able to tolerateoral administration).

The exact amount of a polymorphic form required to achieve an effectiveamount will vary from subject to subject, depending, for example, onspecies, age, and general condition of a subject, severity of the sideeffects or disorder, identity of the particular polymorph, mode ofadministration, and the like. An effective amount may be included in asingle dose (e.g., single oral dose) or multiple doses (e.g., multipleoral doses). In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, any two doses of the multiple doses include different orsubstantially the same amounts of a polymorphic form of sodium benzoatedescribed herein. In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, the frequency of administering the multiple doses to the subjector applying the multiple doses to the tissue or cell is three doses aday, two doses a day, one dose a day, one dose every other day, one doseevery third day, one dose every week, one dose every other week, onedose monthly or one dose every other month. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is one dose per day. In certainembodiments, the frequency of administering the multiple doses to thesubject or applying the multiple doses to the tissue or cell is twodoses per day. In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, biological sample, tissue, or cell. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthree months, six months, or one year. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthe lifetime of the subject, biological sample, tissue, or cell. Incertain embodiments, a dose (e.g., a single dose, or any dose ofmultiple doses) described herein includes independently between 1 mg and3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, orbetween 1 g and 10 g, inclusive, of a polymorphic form of sodiumbenzoate described herein. In certain embodiments, a dose describedherein includes independently between 3 mg and 10 mg, inclusive, of apolymorphic form of sodium benzoate described herein. In certainembodiments, a dose described herein includes independently between 10mg and 30 mg, inclusive, of a polymorphic form of sodium benzoatedescribed herein. In certain embodiments, a dose described hereinincludes independently between 30 mg and 100 mg, inclusive, of apolymorphic form of sodium benzoate described herein. In certainembodiments, a dose described herein includes independently between 100mg and 300 mg, inclusive, of a polymorphic form as described herein. Incertain embodiments, a dose described herein includes independentlybetween 300 mg and 1000 mg, inclusive, of a polymorphic form of sodiumbenzoate described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A polymorphic form or composition, as described herein, can beadministered in combination with one or more additional pharmaceuticalagents (e.g., therapeutically and/or prophylactically active agents)useful in treating and/or reducing the risk for a neuropsychiatricdisorder. The polymorphic forms or compositions can be administered incombination with additional pharmaceutical agents that improve theiractivity (e.g., activity (e.g., potency and/or efficacy) in treatingand/or reducing the risk for a neuropsychiatric disorder in a subject inneed thereof), improve bioavailability, improve safety, reduce drugresistance, reduce and/or modify metabolism, inhibit excretion, and/ormodify distribution in a subject, biological sample, tissue, or cell. Itwill also be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.In certain embodiments, a pharmaceutical composition described hereinincluding a polymorphic form of sodium benzoate described herein and anadditional pharmaceutical agent shows a synergistic effect that isabsent in a pharmaceutical composition including one of the polymorphand the additional pharmaceutical agent, but not both.

The polymorph or composition can be administered concurrently with,prior to, or subsequent to one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies in treating and/orreducing the risk for a neuropsychiatric disorder in a subject.Pharmaceutical agents include therapeutically active agents.Pharmaceutical agents also include prophylactically active agents.Pharmaceutical agents include small organic molecules such as drugcompounds or polymorphic forms thereof (e.g., compounds approved forhuman or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, antibodies, small molecules linked to proteins such asantibodies, glycoproteins, steroids, nucleic acids, DNAs, RNAs,nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides,lipids, hormones, vitamins, and cells. In certain embodiments, theadditional pharmaceutical agent is a pharmaceutical agent useful intreating and/or reducing the risk for a neuropsychiatric disorder in asubject. In certain embodiments, the additional pharmaceutical agent isa pharmaceutical agent approved by a regulatory agency (e.g., the USFDA, EMA, China FDA) for treating and/or reducing the risk for aneuropsychiatric disorder in a subject. In certain embodiments, theadditional pharmaceutical agent is a neuropharmaceutical selected fromthe group consisting of cariprazine, brexpiprazole, iloperidone,pimavanserin, luradisone, butyrophenone, phenothiazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, trifluoperazine,mesoridazine, promazine, triflupromazine, levomepromazine, promethazine,thioxanthene, chlorprothixene, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole,lamotrigine, tetrabenazine, cannabidiol, LY2140023, droperidol,pimozide, butaperazine, carphenazine, eemoxipride, piperacetazine,sulpiride, acamprosate, tetrabenazine, vilazodone, levomilnacipran,vortioxetine fluoxetine, paroxetine, escitalopram, citalopram,sertraline, fluvoxamine, venlafaxine, milnacipram, duloxetine,mirtazapine, mianserin, reboxetine, bupropion, amitriptyline,nortriptiline, protriptyline, desipramine, trimipramine, amoxapine,clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine,selegiline, trazodone, nefazodone, phenelzine, lamatrogine, lithium,topiramate, gabapentin, carbamazepine, oxacarbazepine, valporate,maprotiline, mirtazapine, brofaromine, gepirone, moclobemide, isoniazid,iproniazid, a statin, an amphetamine, modafinil, desoxyn,methamphetamine, cocaine, arecoline, dexmethylphenidate,dextroamphetamine, methylphenidate, lisdexamfetamine dimesylate, mixedsalts amphetamine, atomoxetine, clonidine hydrochloride, guanfacinehydrochloride, arecoline, pemoline, donepezil, tacrine, rivastigmine,memantine, physostigmine, lithium salts, nicotine, arecoline, huperzinealpha, riluzole, vitamin C, vitamin E, carotenoids, tannic acid, andGinkgo biloba extract.

Each additional pharmaceutical agent may be administered at a doseand/or on a time schedule determined for that pharmaceutical agent. Theadditional pharmaceutical agents may also be administered together witheach other and/or with the polymorph or composition described herein ina single dose or administered separately in different doses. Theparticular combination to employ in a regimen will take into accountcompatibility of the polymorph described herein with the additionalpharmaceutical agent(s) and/or the desired therapeutic and/orprophylactic effect to be achieved. In general, it is expected that theadditional pharmaceutical agent(s) in combination be utilized at levelsthat do not exceed the levels at which they are utilized individually.In some embodiments, the levels utilized in combination will be lowerthan those utilized individually.

In certain embodiments, the additional pharmaceutical agent is an agentfor treating and/or reducing the risk for a neuropsychiatric disorder.In certain embodiments, the polymorphic forms of sodium benzoatedescribed herein or pharmaceutical compositions can be administered incombination with a therapy for treating and/or reducing the risk for aneuropsychiatric disorder.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present invention toits fullest extent. The following specific embodiments are, therefore,to be construed as merely illustrative, and not limitative of theremainder of the disclosure in any way whatsoever. All publicationscited herein are incorporated by reference for the purposes or subjectmatter referenced herein.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the polymorphicforms, compounds, compositions, and methods provided herein and are notto be construed in any way as limiting their scope.

Example 1: Preparation of Polymorphic Form #1 of Sodium Benzoate

199.93 mg of sodium benzoate was placed in a flask and 4 mL of methanolwas added to dissolve the sodium benzoate. Unless otherwise indicated,commercially available sodium benzoate was purchased from Merck, FormosaLaboratories Inc., or Sigma Aldrich, and solvents were purchased fromvendors such as Acros, Merck, and Sigma Aldrich. The solution thusformed was kept stirring for 10 min and then filtered to remove anyinsoluble ingredients. The filtrate was evaporated by rotary evaporationto form solid sodium benzoate in a polymorphic form. The solid obtainedwas analyzed by XRPD, TGA, and DSC as described below.

Thermogravimetric Analysis (TGA).

Total weight loss was obtained on a TA Instrument TGA Model Q500. Thesample was heated in an opened aluminum pan at the heating rate of 10°C./min up to the final temperature.

Differential Scanning Calorimetry.

Thermal analysis was performed using a TA Instrument DSC Model Q200. Thesample was heated in an aluminum pan at the heating rate of 10° C./minwith 50 mL/min nitrogen purge up to the final temperature.

X-Ray Powder Diffractometry.

The solid samples were determined by X-ray powder diffractometer (BrukerD8 advance) equipped with LynxEye detector. The instrument parameterswere listed below. Scan: 3° (2θ) to 40° (2θ); Increment: 0.02° (2θ);Scan speed: 0.1-0.3 sec/step (FIGS. 1-24); or scan speed: approximately1 sec/step (FIGS. 25-28); Voltage: 40 KV; Current: 40 mA; Rotation: On;Sample hold: Zero-background sample holder.

The results obtained from the TGA, DSC and X-ray powder diffractometryassays are provided in FIGS. 1-28.

Example 2: Preparation of Polymorphic Form #2

2.005 mg of commercially available sodium benzoate was placed in a roundbottom flask followed by the addition of 150 mL of acetonitrile. Thesuspension thus formed was kept stirring for 2 days and filtered tocollect solid sodium benzoate thus formed. The solid sodium benzoate, ina polymorphic form, was also analyzed by XRPD, TGA, and DSC and theresults are shown in FIGS. 4-6.

Example 3: Preparation of Polymorphic Form #3

2.006 g of commercially available sodium benzoate was placed in a roundbottom flask and 150 mL of isobutanol was added. The suspension thusformed was kept stirring for 6 days and filtered afterwards. The solidsodium benzoate thus formed was collected and analyzed by XRPD, TGA, andDSC. The results are shown in FIGS. 7-9.

Example 4: Preparation of Polymorphic Form #4

2.182 g of commercially available sodium benzoate was placed in a roundbottom flask followed by the addition of 4 mL of water. 20 mL ofisopropyl alcohol was then added gradually and the resulting suspensionwas kept stirring for 3 days and filtered to collect the solid thusformed. The solid collected was analyzed by XRPD, TGA, and DSC. Theresults are shown in FIGS. 10-12.

Example 5: Preparation of Polymorphic Form #5

106.6 mg commercially available sodium benzoate was placed in a roundbottom flask and 70 mL of a mixed solvent containing ethanol and ethylacetate (1:1) was added at 70° C. The resulting solution was keptstirring for 10 min, then cooled to ambient temperature and stirredovernight to allow for formation of solid sodium benzoate in apolymorphic form, which was collected by filtration and analyzed byXRPD, TGA, and DSC. The results are shown in FIGS. 13-15.

Example 6: Preparation of Polymorphic Form #6

2.006 g of commercially available sodium benzoate was placed in a roundbottom flask and 40 mL of methanol was added to dissolve the sodiumbenzoate. 120 mL of acetonitrile was added gradually and the suspensionthus formed was kept stirring. After 2 days, the suspension was filteredand solid obtained was analyzed by XRPD, TGA, and DSC. The results areshown in FIGS. 16-18.

Example 7: Alternative Preparation of Polymorphic Form #4

1-2 mg of either one of the new polymorphic forms #1-3, 5, or 6disclosed herein was slurried in 0.5 mL of acetonitrile withapproximately 6% of water to allow formation of the new polymorphic form#4. It was thus demonstrated that among all new polymorphic formsafforded, polymorphic form #4 was the most thermodynamically stable.

Example 8: Scale-Up Preparation of Polymorphic Form #4

50 g of commercially available sodium benzoate (purchased from Merck)was placed in a round bottom flask followed by the addition of 92 mL ofwater. 688 mL of isopropyl alcohol was slowly added and the resultingsuspension was kept stirring with an overhead stirrer for 4 days andfiltered to collect 22.3 g of the solid.

Example 9: Stability Test of Polymorphic Form #4 Under High HumidityCondition

500 mg of each of sodium benzoate from Merck and Formosa Laboratories,and polymorphic form #4 was stored under high humidity condition (>90%RH) for 5 days and analyzed by XRPD. The results indicated that, after 5days, there were significant changes to the XRPD patterns with peaks ata reflection angle 2θ of approximately 6.2, 16.5, and 24.5 degrees andthe appearance of a new peak at 22.9 degrees of sodium benzoate fromMerck and Formosa Laboratories, while no change to the XRPD pattern ofnew polymorphic form #4 was observed. The results are shown in FIG. 19.It was thus shown that polymorphic #4 was more stable than the testedcommercial sodium benzoate products under high humidity conditions.

Example 10: Stability Test of Polymorphic Form #4 Combined withClozapine Under High Humidity Conditions

500 mg of each of sodium benzoate from Merck and new polymorphic form #4combined with 300 mg of clozapine was stored under high humiditycondition (>90% RH) for 5 days and analyzed by XRPD. The resultsrevealed that, after 5 days, there were significant changes to the XRPDpattern with peaks at a reflection angle 2θ of approximately 6.2, 14.9,15.9, 16.5, 20.5, 22.6, and 25.1 degrees and the appearance of a newpeak at 22.9 degrees of sodium benzoate from Merck combined withclozapine. No change to the XRPD pattern of new polymorphic form #4combined with clozapine was observed. The results are shown in FIGS.20-21. It was thus illustrated that, when combined with a secondtherapeutic agent, the use of polymorphic form #4 was more suitable thanthe tested commercial sodium benzoate products.

Example 11: Further Comparison of Polymorphic Form #4 with SodiumBenzoate from Merck and Sigma Aldrich

New polymorphic form #4, sodium benzoate from Merck, and sodium benzoatefrom Sigma Aldrich were analyzed and compared by XRPD. The results, asshown in FIG. 22, indicated that the XRPD patterns of these twocommercial sodium benzoate samples from Merck and Sigma Aldrich muchoverlapped with each other. New polymorphic form #4 was found to be themost thermodynamically stable polymorphic form of sodium benzoate,compared to the less thermodynamically stable polymorphic form from thecommercially available sodium benzoate (Merck, Formosa Laboratories, andSigma Aldrich).

Example 12: Solubility of Polymorphic Form #4 in Water

To around 1 g of each of new polymorphic form #4, sodium benzoate fromMerck, and sodium benzoate from Sigma Aldrich in a vial was added watertill maximum solubility was reached. The results showed that the maximumwater solubility of new polymorphic form #4 (666 mg/ml) was higher thanthat of sodium benzoate from Merck (500 mg/ml) and Sigma Aldrich (454mg/ml). Therefore, the solubility of the polymorphic form #4 of sodiumbenzoate of the invention is about 1.3 to 1.5 times higher than thecommercially available sodium benzoate products.

Example 13: Stability Tests of Commercially Available Sodium Benzoateand Polymorphic Form #4 of Sodium Benzoate 1. Stress Testing Under HighHumidity Conditions

Another stability test was held with 500 mg of commercially availablesodium benzoate from Merck or the polymorphic form #4 of sodium benzoateof the invention independently combined with 100 mg of clozapine, storedunder high humidity condition (>90% RH), at room temperature for 8 days.On day 8, the XRPD pattern of the combination of commercially availablesodium benzoate and clozapine showed an additional new peak at 11°, asshown by an arrow in FIG. 23-24. However, the additional peak at 11° wasnot found in the XRPD pattern of the combination of the polymorphic form#4 of sodium benzoate of the invention and clozapine. In the followingexperiments, the appearance of the peak at 11° was deemed asdeterioration of clozapine polymorph in the combination of clozapine andcommercially available sodium benzoate.

2. Stability of Combination of Polymorphic Form #4 of Sodium Benzoate ofthe Invention and Clozapine, and Other Excipients

Since humidity is a stability issue for the combination of sodiumbenzoate compound and clozapine, several excipients were chosen to testtheir influences on the stability under high humidity condition (>90%RH, room temperature). The results are shown in the Tables 1 and 2.

Comparing with boric acid, sodium alginate has a better effect instabilizing the combination of sodium benzoate (purchased from Merck)and clozapine (see Table 1). In addition, the 11° peak, which indicatesthe deterioration of the combination of sodium benzoate (purchased fromMerck) and clozapine, does not appear until day 30 when high dose ofchitosan (60 mg) or sodium citrate (60 mg) further added in thecomposition (see Table 2).

TABLE 1 Stability test results under high humidity condition (>90% RH,room temperature) of sodium benzoate and clozapine mixed with differentexcipients Sample 1 2 3 4 Sodium benzoate (Merck) (mg) 500 500 500 500Clozapine (mg) 300 300 300 300 Boric acid (mg) 20 40 — — Sodium alginate(mg) — — 20 40 TOTAL (mg) 820 840 820 840 Appearance of peak at 11° Day5 Day 5 Day 11 Day 11

TABLE 2 Stability test results under high humidity condition (>90% RH,room temperature) of sodium benzoate and clozapine mixed with differentexcipients Sample 5 6 7 8 9 10 11 12 13 14 Sodium benzoate (Merck) (mg)500 500 500 500 500 500 500 500 500 500 Clozapine (mg) 300 300 300 300300 300 300 300 300 300 Sodium alginate (mg) 40 40 40 40 40 40 40 40 4040 Chitosan (mg) 30 60 — — — — — — — — Sodium hyaluronate (mg) — — 7.515 — — — — — — Sodium stearyl fumarate (mg) — — — — 7.5 15 — — — —Sodium citrate (mg) — — — — — — 30 60 — — Sodium starch glycolate (mg) —— — — — — — — 30 60 TOTAL (mg) 870 900 847.5 855 847.5 855 870 900 870900 Appearance of peak at 11° Day 20 Day 30 Day 20 Day 13 Day 11 Day 11Day 20 Day 30 Day 11 Day 11

Example 14: Preparation of Tablets Comprising Sodium Benzoate Compoundand Clozapine 1. Wet Granulation

The active ingredients (e.g. any of the sodium benzoate compounds andclozapine) and excipients were milled and sieved by a 40-mesh screenseparately. The milled and sieved powders were mixed in a mortar. 75%ethanol, which was used as a binder solution, was added slowly into themortar to perform wet granulation. The obtained wet mass was screened bya 20-mesh screen for coarse screening. Then the moist granules weredried at 50° C. for 3 hours. The dried granules were further sievedtwice: (1) by a 40-mesh screen, and the granules larger than 40-meshwere kept; and (2) by a 20-mesh screen, and the granules passed thescreen were kept. After sieving with the 40- and 20-mesh screens, thegranules having sizes between 20 and 40 meshes were obtained. Theresulted granules were then blended with magnesium stearate as alubricant for approximately 3 minutes, and the blend was compressed byZP01 Single punch tablet press (Taizhou Liming Pharmaceutical MachineryCo., Ltd.) into tablets. The obtained tablets were weighted, and theirhardness, friability, disintegration time and dissolution release timewere tested.

2. Hardness Test

The obtained tablets were subjected to a hardness test, and the power(kg) needed for breaking the tested tablet was recorded. The harness oftablets was controlled between 5 to 10 kg.

3. Friability Test

Ten tablets were put in a tablet friability apparatus and rotated at25±1 rpm for 100 circles. The test was determined as failed if any ofthe tested tablets were broken. When the tablets were not broken, theywould be weighted to calculate their weight loss (%). The weight loss(%) should be lower than 1%.

4. Disintegration Test

Six tablets were put into water at 37±2° C. The test was determined asfailed if these tablets were not disintegrated within 30 minutes. Thedisintegration time (minutes) of these tablets was recorded.

5. Dissolution Test

The dissolution test was performed based on the USP method fordissolution of clozapine. Six tablets were added into the dissolutionmedium (acetate buffer, pH 4.0) and subjected to the dissolution test.The volume of the dissolution medium was 500 mL and the rotation speedwas of 100 rpm. The test was determined as failed if these tablets werenot dissolved within 30 minutes. The dissolution time (minutes) of thesetablets was recorded.

Both sodium alginate and sodium citrate enhance the immediate releaseeffect, but the tablet formulations 1-2, which comprise sodium alginateand sodium citrate, flaked off during the dissolution test, and theaddition of sodium starch glycolate (SSG) as a disintegrating agentimproved this defect, as shown in Table 3.

TABLE 3 Tablet formulations Formulation 1 2 3 Sodium benzoate (Merck)(mg) 500 500 500 Clozapine (mg) 300 200 300 Sodium alginate (mg) 60 6060 Sodium citrate (mg) 60 60 60 Magnesium stearate (mg) 10 10 10 Sodiumstarch glycolate (mg) — — 90 TOTAL (mg) 930 830 1020 Hardness (kg) 7~813-14 10 Friability (%) 0.73 0.51 0.6 Disintegration time (min) 20 19 13Dissolution release time (min) <30 <30 15

Tablet formulations comprising the combination of clozapine andcommercially available sodium benzoate (purchased from Merck) or thepolymorphic form #4 sodium benzoate obtained from Example 4, as shown inTables 4 and 5, were then examined. The results showed that the tabletscomprising the polymorphic form #4 of sodium benzoate of the inventionhad shorter disintegration time and dissolution release time, which werebenefit for preparation of immediate release dosage form of drugs.

TABLE 4 Tablet formulations comprising commercially available sodiumbenzoate and clozapine Formulation 4 5 6 7 8 9 10 11 Sodium benzoate(Merck) (mg) 500 500 500 500 500 500 500 500 Clozapine (mg) 300 300 300300 200 200 200 200 Sodium alginate (mg) 50 70 50 70 50 70 50 70 Sodiumcitrate (mg) 50 70 60 60 50 70 60 60 Magnesium stearate (mg) 5 15 10 105 15 10 10 Sodium starch glycolate (mg) 80 100 100 80 80 100 100 80TOTAL (mg) 985 1055 1020 1020 885 955 920 920 Hardness (kg)  9~10  9~10 9~10  9~10 10~11 10~11 10~11 10~11 Friability (%) 0.42 0.50 0.76 0.530.36 0.38 0.40 0.34 Disintegration time (min) 16~17 16~18 13~14 15~1611~12 11~12 11~12 13~14 Dissolution release time (min) 14~15 15~16 13~1415~16 11~12 12~13 11~12 13~14

TABLE 5 Tablet formulations comprising the polymorphic form #4 of sodiumbenzoate of the invention and clozapine Formulation 12 13 14 15 16 17 1819 Polymorphic form #4 of 500 500 500 500 500 500 500 500 sodiumbenzoate (mg) Clozapine (mg) 300 300 300 300 200 200 200 200 Sodiumalginate (mg) 50 70 50 70 50 70 50 70 Sodium citrate (mg) 50 70 60 60 5070 60 60 Magnesium stearate (mg) 5 15 10 10 5 15 10 10 Sodium starchglycolate (mg) 80 100 100 80 80 100 100 80 TOTAL (mg) 985 1055 1020 1020885 955 920 920 Hardness (kg) 6~7 6~7 6~7 6~7 6~7 6~7 6~7 6~7 Friability(%) 0.68 0.71 0.67 0.63 0.52 0.69 0.66 0.78 Disintegration time (min)5~6 6~7 5~6 6~7 5~6 6~7 5~6 5~6 Dissolution release time (min) 8~9 8~98~9 8~9 7~8 8~9 8~9 8~9

Example 15: Comparative Features of Various Polymorph Forms of SodiumBenzoate

Polymorph forms #1, 2, 3 and 6 (“polymorph forms #1-3 and 6”) wereprepared following the methods disclosed above (Examples 1, 2, 3, and 6,respectively). Another sodium benzoate polymorph was prepared followingthe conditions disclosed in Howard et al. (Crystal Growth and Design,Vol. 9, pages 3964-3975; see, e.g., Section 2.4 and FIG. 4) (“polymorph#7”), which differ from the conditions used for preparing Forms #1-3 and6 in at least the time frame for polymorph formation, solvent used fordissolving sodium benzoate, etc. Specifically, Howard discloses a sodiumbenzoate polymorph prepared over approximately 40 hours by: antisolventcrystallization performed using sodium benzoate in pure water with aninitial concentration of 545 mg/mL; heating the system from 20 to 25° C.and kept at 25° C. until all the crystals dissolved, resulting in aclear solution; then adding propan-2-ol (IPA) was then added using adosing rate within the range 0.3-2 g/min, reaching a final volume ratioof IPA/water of 5:1. Howard, Section 2.4.

Polymorph forms #1-3 and 6 involve a process of preparation comprising:(i) dissolving sodium benzoate in a polar solvent that is not purelywater (e.g., either methanol, acetonitrile, or isobutanol; oracetonitrile followed by addition of methanol) to form a slurry, (ii)stirring the slurry for approximately 10 minutes to approximately 6 days(e.g., 10 minutes, 2 days, or 6 days (in contrast with the 40 hours forpreparing polymorph #7)), and (iii) filtering and collecting thepolymorphic form of sodium benzoate thus formed. The Howard polymorph isprepared using a final solvent ratio of IPA/water of 5:1, which isdifferent from the polar solvents used for preparing polymorph forms#1-3 and 6 (shown in Examples 1, 2, 3, and 6, respectively).

XRPD patterns of polymorph forms #1-3 and 6, obtained using a period ofa scan speed of about 1.0 second per step, were different from the XRPDpattern of the different polymorph obtained under the same XRPD scanspeed conditions in Howard prepared using conditions of Section 2.4 andFIG. 4. A comparison of the XRPD patterns of polymorph forms #1-3 and 6with polymorph #7 of Howard is shown in Tables 6, 7, 8, and 9 below, allobtained under the same XRPD scan speed conditions (using a period of ascan speed of about 1.0 second per step). Specifically, the peaks of theXRPD pattern for polymorph #1 are shown below in Table 6, and the XRPDpattern is shown in FIG. 25. The peaks of the XRPD pattern for polymorph#2 are shown below in Table 7, and the XRPD pattern is shown in FIG. 26.The peaks of the XRPD pattern for polymorph #3 are shown below in Table7, and the corresponding XRPD pattern is shown in FIG. 27. The peaks ofthe XRPD pattern for polymorph #3 are shown below in Table 8, and thecorresponding XRPD pattern is shown in FIG. 27. The peaks of the XRPDpattern for polymorph #6 are shown below in Table 9, and thecorresponding XRPD pattern is shown in FIG. 28. The peaks of the XRPDpattern for polymorph #7 are shown below in Tables 6, 7, 8, and 9, andthe XRPD pattern for polymorph #7 is shown in FIG. 29.

TABLE 6 XRPD Peaks in Angle (2θ) Polymorph 3.6, 4.2, 5.9, 6.8, 7.5, 8.5,9.2, 11.1, 11.7, 12.4, 14.9, 15.9, Form #1 16.6, 17.6, 18.8, 19.4, 20.4,21.6, 22.9, 23.7, 24.7, 25.1, 25.8, 26.1, 26.6, 27.7, 28.1, 29.1, 29.4,29.7, 30.2, 30.6, 30.9, 31.5, 32.4, 32.9, 33.6, 34.2, 35.7, 38.6, 39.6Polymorph 4.2, 5.8, 6.8, 8.5, 10.0, 11.7, 12.8, 14.8, 15.7, 16.4, 17.6,#7 18.7, 19.4, 20.4, 21.2, 22.5, 23.6, 25.0, 25.9, 28.1, 29.0, 29.7,30.2, 31.1, 32.4, 33.0, 34.2, 35.7

TABLE 7 XRPD Peaks in Angle (2θ) Polymorph 3.7, 5.9, 6.8, 7.5, 8.9,11.1, 14.9, 17.6, 22.7, 23.5, 24.8, Form #2 26.2, 26.6, 27.6, 28.3,29.3, 30.2, 30.9, 32.2, 32.9, 34.0, 35.7, 37.8 Polymorph 4.2, 5.8, 6.8,8.5, 10.0, 11.7, 12.8, 14.8, 15.7, 16.4, #7 17.6, 18.7, 19.4, 20.4,21.2, 22.5, 23.6, 25.0, 25.9, 28.1, 29.0, 29.7, 30.2, 31.1, 32.4, 33.0,34.2, 35.7

TABLE 8 XRPD Peaks in Angle (2θ) Polymorph 3.7, 5.9, 6.3, 6.8, 7.5, 9.4,11.7, 16.4, 17.7, 23.6, 24.5, Form #3 25.7, 26.7, 27.7, 28.4, 29.0,29.4, 30.2, 30.4, 31.0, 31.2, 32.3, 34.2, 35.4, 35.9 Polymorph 4.2, 5.8,6.8, 8.5, 10.0, 11.7, 12.8, 14.8, 15.7, 16.4, 17.6, #7 18.7, 19.4, 20.4,21.2, 22.5, 23.6, 25.0, 25.9, 28.1, 29.0, 29.7, 30.2, 31.1, 32.4, 33.0,34.2, 35.7

TABLE 9 XRPD Peaks in Angle (2θ) Polymorph 3.7, 4.2, 5.6, 5.9, 6.6, 7.4,8.4, 9.4, 11.2, 12.5, 14.8, 17.6, Form #6 18.6, 21.6, 22.8, 23.6, 25.1,26.3, 26.5, 27.1, 28.2, 29.5, 30.2, 31.1, 31.3, 32.0, 33.0, 34.0, 35.7,38.0 Polymorph 4.2, 5.8, 6.8, 8.5, 10.0, 11.7, 12.8, 14.8, 15.7, 16.4,17.6, #7 18.7, 19.4, 20.4, 21.2, 22.5, 23.6, 25.0, 25.9, 28.1, 29.0,29.7, 30.2, 31.1, 32.4, 33.0, 34.2, 35.7

Polymorph forms #1-3 and 6, obtained using a period of a scan speed ofabout 1.0 second per step, have at a reflection angle 2θ of at least thecharacteristic XRPD peaks (°) of: approximately 3.6, 7.5, 26.6, and29.4; which are not present in polymorph #7. Polymorph forms #1-3,obtained using a period of a scan speed of about 1.0 second per step,have at a reflection angle 2θ of at least the characteristic XRPD peaks(°) of: approximately 5.9, 6.8, 17.6, 27.6, 30.2, 30.9, and 32.3; whichare not present in polymorph #7. Polymorph forms #1, 2, and 6, obtainedusing a period of a scan speed of about 1.0 second per step, have at areflection angle 2θ of at least the characteristic XRPD peaks (°) of:approximately 11.1, 14.9, 26.2, 32.9, and 35.7; which are not present inpolymorph #7. Polymorph forms #1 and 6, obtained using a period of ascan speed of about 1.0 second per step, have at a reflection angle 2θof at least the characteristic XRPD peaks (°) of: approximately 12.4 and22.9; which are not present in polymorph #7.

EQUIVALENTS AND SCOPE

In the claims, articles such as “a,” “an,” and “the” may mean one ormore than one unless indicated to the contrary or otherwise evident fromthe context. Claims or descriptions that include “or” between one ormore members of a group are considered satisfied if one, more than one,or all of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should be understood that, in general, where the invention, oraspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A polymorphic form of sodium benzoate, which hasan X-ray diffraction pattern comprising characteristic peaks at areflection angle 2θ of approximately 5.9, 30.2, and 31.2 degrees.
 2. Thepolymorphic form of sodium benzoate of claim 1, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 3.6, 7.2, 7.5, 14.9, 15.9, 16.6,17.6, 18.8, 20.4, 22.9, 23.7, 25.1, 25.8, 26.6, 28.1, 29.1, 29.4, 29.7,31.5, 32.9, 34.2, and 35.7 degrees.
 3. The polymorphic form of sodiumbenzoate of claim 1, wherein the X-ray diffraction pattern furthercomprises characteristic peaks at a reflection angle 2θ of approximately3.7, 6.8, 7.5, 11.3, 11.6, 17.6, 22.7, 23.5, 26.2, 27.6, 28.3, 29.3,32.2, 32.9, 34.0, and 35.7 degrees
 4. The polymorphic form of sodiumbenzoate of claim 1, wherein the X-ray diffraction pattern furthercomprises characteristic peaks at a reflection angle 2θ of approximately3.7, 6.3, 6.8, 7.5, 11.7, 17.7, 23.6, 24.5, 26.5, 27.0, 27.7, 28.4,29.0, 31.0, 32.3, 34.2, and 35.9 degrees.
 5. The polymorphic form ofsodium benzoate of claim 1, wherein the X-ray diffraction patternfurther comprises characteristic peaks at a reflection angle 2θ ofapproximately 4.3, 7.1, 8.6, 10.1, 10.7, 12.9, 13.8, 14.4, 17.2, 17.7,18.5, 21.5, 22.0, 22.6, 23.7, 25.1, 25.9, 26.2, 26.9, 27.9, 28.2, 28.8,29.1, 29.7, 33.2, 34.9, 35.8, 36.1, and 39.3 degrees.
 6. A polymorphicform of sodium benzoate, which has an X-ray diffraction patterncomprising characteristic peaks at a reflection angle 2θ ofapproximately 3.7, 5.9, and 26.6 degrees.
 7. The polymorphic form ofsodium benzoate of claim 6, wherein the X-ray diffraction patternfurther comprises characteristic peaks at a reflection angle 2θ ofapproximately 5.5, 6.7, 7.4, 12.5, 14.7, 16.5, 17.7, 22.0, 23.6, 24.6,25.8, 27.6, 28.4, 30.2, 31.1, 32.3, 34.3, and 35.9 degrees.
 8. Thepolymorphic form of sodium benzoate of claim 6, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 6.6, 7.4, 9.4, 11.2, 12.5, 22.8,25.1, 26.3, 28.2, 29.5, 30.2, 31.1, 31.2, 33.0, and 34.0 degrees.
 9. Apolymorphic form of sodium benzoate, which has an X-ray diffractionpattern comprising characteristic peaks at a reflection angle 2θ ofapproximately 3.6, 7.5, 26.6, and 29.4 degrees; wherein the X-raydiffraction pattern is determined by a period of a scan speed of about1.0 second per step.
 10. The polymorphic form of sodium benzoate ofclaim 9, wherein the X-ray diffraction pattern further comprisescharacteristic peaks at a reflection angle 2θ of approximately 5.9, 6.8,17.6, 27.6, 30.2, 30.9, and 32.3 degrees.
 11. The polymorphic form ofsodium benzoate of claim 9, wherein the X-ray diffraction patternfurther comprises characteristic peaks at a reflection angle 2θ ofapproximately 11.1, 14.9, 26.2, 32.9, and 35.7 degrees.
 12. Thepolymorphic form of sodium benzoate of claim 9, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 12.4 and 22.9 degrees.
 13. Thepolymorphic form of sodium benzoate of claim 9, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 4.2, 8.5, 9.2, 11.1, 11.7, 12.4,14.9, 15.9, 16.6, 18.8, 19.4, 20.4, 21.6, 22.9, 23.7, 24.7, 25.1, 25.8,26.1, 28.1, 29.1, 29.7, 30.6, 31.5, 32.9, 33.6, 34.2, 35.7, 38.6, and39.6 degrees.
 14. The polymorphic form of sodium benzoate of claim 9,wherein the X-ray diffraction pattern further comprises characteristicpeaks at a reflection angle 2θ of approximately 8.9, 11.1, 14.9, 22.7,23.5, 24.8, 26.2, 28.3, 32.9, 34.0, 35.7, and 37.8 degrees.
 15. Thepolymorphic form of sodium benzoate of claim 9, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 6.3, 9.4, 11.7, 16.4, 23.6, 24.5,25.7, 28.4, 29.0, 30.4, 31.0, 31.2, 34.2, 35.4, and 35.9 degrees. 16.The polymorphic form of sodium benzoate of claim 9, wherein the X-raydiffraction pattern further comprises characteristic peaks at areflection angle 2θ of approximately 4.2, 5.6, 5.9, 6.6, 8.4, 9.4, 12.5,17.6, 18.6, 21.6, 22.8, 23.6, 25.1, 27.1, 28.2, 30.2, 31.1, 31.3, 32.0,34.0, and 38.0 degrees.
 17. A polymorphic form of sodium benzoate, whichis prepared by a process comprising (i) dissolving sodium benzoate in apolar solvent comprising methanol, acetonitrile, or isobutanol, or acombination thereof, to form a slurry, and (ii) stirring the slurry forapproximately 10 minutes to approximately 6 days to produce thepolymorphic form of sodium benzoate, and (iii) filtering and collectingthe polymorphic form of sodium benzoate thus formed.
 18. The polymorphicform of sodium benzoate of claim 17, wherein in step (i), the. solventcomprises methanol, acetonitrile, or isobutanol, or a combinationthereof.
 19. The polymorphic form of sodium benzoate of claim 17,wherein in step (i), the solvent comprises methanol and wherein theprocess further comprises adding acetonitrile after the sodium benzoateis dissolved in the solvent in step (i).
 20. The polymorphic form ofsodium benzoate of any one of claims 17-19, wherein in step (i) thesolvent comprises methanol, and wherein in step (ii) the stirring of theslurry is for approximately 10 minutes.
 21. The polymorphic form ofsodium benzoate of claim 17 or 18, wherein in step (i), the solventcomprises acetonitrile, and wherein in step (ii), the stirring of theslurry is for approximately 2 days.
 22. The polymorphic form of sodiumbenzoate of claim 17 or 18, wherein in step (i), the solvent comprisesisobutanol, and wherein in step (ii), the stirring of the slurry is forapproximately 6 days.
 23. The polymorphic form of sodium benzoate ofclaim 19, wherein in step (ii) the stirring of the slurry is forapproximately 2 days.
 24. A composition, comprising (i) an effectiveamount of a polymorphic form of sodium benzoate of any one of claims1-22, and (ii) a pharmaceutically acceptable carrier, excipient,diluent, binder, additive, filler, and lubricant, or a mixture thereof.25. The composition of claim 23, further comprising aneuropharmaceutical.
 26. The composition of claim 24, wherein theneuropharmaceutical is selected from the group consisting ofcariprazine, brexpiprazole, iloperidone, pimavanserin, luradisone,butyrophenone, phenothiazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,promazine, triflupromazine, levomepromazine, promethazine, thioxanthene,chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine,olanzapine, risperidone, quetiapine, ziprasidone, amisulpride,asenapine, paliperidone, aripiprazole, lamotrigine, tetrabenazine,cannabidiol, LY2140023, droperidol, pimozide, butaperazine,carphenazine, eemoxipride, piperacetazine, sulpiride, acamprosate,tetrabenazine, vilazodone, levomilnacipran, vortioxetine, fluoxetine,paroxetine, escitalopram, citalopram, sertraline, fluvoxamine,venlafaxine, milnacipram, duloxetine, mirtazapine, mianserin,reboxetine, bupropion, amitriptyline, nortriptiline, protriptyline,desipramine, trimipramine, amoxapine, clomipramine, desipramine,doxepin, isocarboxazid, tranylcypromine, selegiline, trazodone,nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin,carbamazepine, oxacarbazepine, valporate, maprotiline, mirtazapine,brofaromine, gepirone, moclobemide, isoniazid, iproniazid, a statin, anamphetamine, modafinil, desoxyn, methamphetamine, cocaine, arecoline,dexmethylphenidate, dextroamphetamine, methylphenidate, lisdexamfetaminedimesylate, mixed salts amphetamine, atomoxetine, clonidinehydrochloride, guanfacine hydrochloride, arecoline, pemoline, donepezil,tacrine, rivastigmine, memantine, physostigmine, lithium salts,nicotine, arecoline, huperzine alpha, selegiline, riluzole, sarcosine,vitamin C, vitamin E, carotenoids, tannic acid, and Ginkgo bilobaextract.
 27. The composition of any one of claims 22-25, wherein thepolymorphic form of sodium benzoate and the neuropharmaceutical in thecomposition are at a ratio of 1:1 to 100:1 by weight.
 28. A compositionof claim 24 or 25, wherein the neuropharmarceutical is clozapine,donepezil, sarcosine, or tannic acid.
 29. The composition of any one ofclaims 23-27, wherein the composition is a pharmaceutical composition, anutraceutical composition, a health food, or a medical food.
 30. Amethod of treating or reducing the risk for a neuropsychiatric disorderin a subject, the method comprising administering to a subject in needthereof a therapeutically effective amount of a polymorphic form ofsodium benzoate of any one of claims 1-22.
 31. The method of claim 29,wherein the neuropsychiatric disorder is selected from the groupconsisting of schizophrenia, psychotic disorders, Alzheimer's disease,dementia, frontotemporal dementia, mild cognitive impairment, benignforgetfulness, closed head injury, autistic spectrum disorders(Asperger's disorder included), attention deficit hyperactivitydisorders, obsessive compulsive disorder, tic disorders, childhoodlearning disorders, premenstrual syndrome, depressions, suicidalideation, suicidal behavior, bipolar disorders, anxiety disorders,post-traumatic stress disorder, chronic pain, eating disorders,addiction disorders, personality disorders, Parkinson's disorder,Huntington's disorder, multiple sclerosis, and amyotrophic lateralsclerosis.
 32. A method for preparing a polymorphic form of sodiumbenzoate, the method comprising: (i) dissolving an excess amount ofsodium benzoate in a single or mixed solvent to form a saturatedsolution at ambient pressure and temperature, (ii) filtrating thesaturated solution to remove insoluble components; (iii) evaporating thesaturated solution obtained in (ii) to form a polymorphic form of sodiumbenzoate at ambient or reduced pressure and at an elevated temperatureof approximately 40-110° C.; and (iv) collecting the polymorphic form ofsodium benzoate formed in (iii).
 33. A method for preparing apolymorphic form of sodium benzoate, the method comprising: (i)dissolving sodium benzoate in a single or mixed solvent at a temperatureranging from about 50-110° C. to form a solution; (ii) cooling thesolution to ambient temperature while stirring; (iii) placing the cooledsolution at ambient temperature to allow formation of a polymorphic formof sodium benzoate; and (iv) collecting the polymorphic form of sodiumbenzoate formed in (iii).
 34. A method for preparing a polymorphic formof sodium benzoate, the method comprising: (i) placing sodium benzoateat a relative humidity (RH) greater than about 90% for about 1 to 10days, during which a polymorphic form of sodium benzoate forms; and (ii)collecting the polymorphic form of sodium benzoate formed in (i).
 35. Amethod for preparing a polymorphic form of sodium benzoate, the methodcomprising: (i) preparing a slurry of sodium benzoate in a single ormixed solvent; (ii) stirring the slurry for 6 hours to 10 days, duringwhich a polymorphic form of sodium benzoate forms; and (iii) collectingthe polymorphic form of sodium benzoate formed in (ii).
 36. A method forpreparing a polymorphic form of sodium benzoate, the method comprising:(i) dissolving sodium benzoate in a single or mixed solvent to form asolution; (ii) mixing an anti-solvent with the solution obtained in (i)to form a slurry, wherein the volume ratio between the anti-solvent andthe solution in (i) is about 4:1 to 15:1; (iii) stirring the slurry atambient pressure and temperature for about 2-10 days, during which apolymorphic form of sodium benzoate forms; and (iv) collecting thepolymorphic form of sodium benzoate formed in (iii).
 37. A method forpreparing a polymorphic form of sodium benzoate, the method comprising:(i) preparing a slurry of the polymorphic form of sodium benzoate of anyone of claims 2, 3, 4, 6, 7, and 8 in a single or mixed solvent in thepresence of about 2-10% of water; (ii) stirring the slurry at ambientpressure and temperature for about 2 to 10 days, during which apolymorphic form of sodium benzoate forms; and (iii) collecting thepolymorphic form of sodium benzoate formed in (iii).
 38. A method forpreparing a polymorphic form of sodium benzoate, the method comprising:(i) dissolving sodium benzoate in a polar solvent comprising methanol,acetonitrile, or isobutanol, or a combination thereof, to form a slurry;(ii) stirring the slurry for approximately 10 minutes to approximately 6days to produce the polymorphic form of sodium benzoate, and (iii)filtering and collecting the polymorphic form of sodium benzoate thusformed.
 39. The method of claim 38, wherein in step (i), the polarsolvent comprises methanol, acetonitrile, or isobutanol, or acombination thereof,
 40. The method of claim 38 or 39, wherein in step(i), the solvent comprises methanol and wherein the method furthercomprises adding acetonitrile after the sodium benzoate is dissolved inthe solvent in step (i).
 41. The method of any one of claims 38-40,wherein in step (i) the solvent comprises methanol, and wherein in step(ii) the stirring of the slurry is for approximately 10 minutes.
 42. Themethod of claim 38 or 39, wherein in step (i), the solvent comprisesacetonitrile, and wherein in step (ii), the stirring of the slurry isfor approximately 2 days.
 43. The method of claim 38 or 39, wherein instep (i), the solvent comprises isobutanol, and wherein in step (ii),the stirring of the slurry is for approximately 6 days.
 44. The methodof claim 40, wherein in step (ii) the stirring of the slurry is forapproximately 2 days.
 45. A pharmaceutical composition comprising 50 to1000 mg of a sodium benzoate compound, 25 to 300 mg of clozapine, and apharmaceutically acceptable excipient, wherein the pharmaceuticalcomposition is in a solid dosage form.
 46. The pharmaceuticalcomposition of claim 45, wherein the sodium benzoate compound is inamorphous form, in polymorphic forms, or a combination thereof.
 47. Thepharmaceutical composition of claim 45 or 46, wherein the sodiumbenzoate compound comprises a polymorphic form of sodium benzoate, whichis characterized by an X-ray powder diffraction pattern comprisingcharacteristic peaks at a reflection angle 2θ of about 5.9, 30.2, and31.2 degrees.
 48. The pharmaceutical composition of claim 47, whereinthe polymorphic form of sodium benzoate is characterized by an X-raypowder diffraction pattern further comprising characteristic peaks at areflection angle 2θ of about 4.3, 7.1, 8.6, 10.1, 10.7, 12.9, 13.8,14.4, 17.2, 17.7, 18.5, 21.5, 22.0, 22.6, 23.7, 25.1, 25.9, 26.2, 26.9,27.9, 28.2, 28.8, 29.1, 29.7, 33.2, 34.9, 35.8, 36.1, 39.3 degrees. 49.The pharmaceutical composition of any one of claims 45-48, wherein theexcipient is selected from the group consisting of boric acid, sodiumalginate, sodium citrate, sodium hyaluronate, chitosan, magnesiumstearate, sodium stearyl fumarate, colloidal silicon dioxide, talc,sodium starch glycolate, croscarmellose, crospovidone, and tannic acid.50. The pharmaceutical composition of claim 45, which comprises 50 to1000 mg of sodium benzoate, 25-300 mg of clozapine, 50-500 mg of sodiumalginate, 50-400 mg of sodium citrate, 5-100 mg of magnesium stearate,and 80-200 mg of sodium starch glycolate.
 51. The pharmaceuticalcomposition of any one of claims 45-50, wherein the solid dosage form isselected from the group consisting of tablet, dragee, capsule, pill,powder, and granule.
 52. The pharmaceutical composition of claim 51,wherein the solid dosage form further comprises a film coating.
 53. Amethod for treating and/or reducing the risk of a neuropsychiatricdisorder, comprising administering to a subject in need thereof thepharmaceutical composition of any one of claims 45-52.
 54. The method ofclaim 52, wherein the neuropsychiatric disorder is selected fromschizophrenia, psychotic disorders, Alzheimer's disease, dementia,frontotemporal dementia, mild cognitive impairment, benignforgetfulness, closed head injury, autistic spectrum disorder,Asperger's disorder, attention deficit hyperactivity disorders,obsessive compulsive disorder, tic disorders, childhood learningdisorders, premenstrual syndrome, depression, suicidal ideation and/orbehaviors, bipolar disorder, anxiety disorders, post-traumatic stressdisorder, chronic pain, eating disorders, addiction disorders,personality disorders, Parkinson's disorder, Huntington's disorder,multiple sclerosis or amyotrophic lateral sclerosis.
 55. The method ofclaim 53 or 54, wherein the subject is a human patient having, suspectedof having, or at risk for the neuropsychiatric disorder.
 56. The methodof any one of claims 53-55, which is administered to the subject by asystemic route.
 57. The method of claim 56, wherein the systemic routeis enteral administration or parenteral administration.
 58. The methodof any one of claims 53-57, wherein the subject is administered thepharmaceutical composition at a frequency of four times a day to onetime two months.
 59. The method of any one of claims 53-58, wherein thesubject is treated concurrently with, prior to, or subsequent to one ormore additional therapeutic agents for treating and/or reducing the riskfor the neuropsychiatric disorder.